Drug Absorption PDF

CHAPTER 8
Bioavailability, Bioequivalence, and Drug Selection
Author: Rasma Chereson Reviewer: Umesh Banakar
OBJECTIVES
1. Given sufficient data to compare an oral product with another oral product or an IV product, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) professional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC, T p and ( Cp ) max ). The student will write (V) a professional consult using the above calculations.
2.
Basic Pharmacokinetics
Copyright 1996 Michael C. Makoid All Rights Reserved
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8.1 Bioavailability, Bioequivalence and Drug Product Selection

Bioavailability and bioequivalence of drug products, and drug product selection have emerged as critical issues in pharmacy and medicine during the last three decades. Concern about lowering health care costs has resulted in a tremendous increase in the use of generic drug products; currently about one half of all prescriptions written are for drugs that can be substituted with a generic product (1). Over 80% of the approximately 10,000 prescription drugs available in 1990 were available from more than one source (2). With the increasing availability and use of generic drug products, health care professionals are confronted with an ever-larger array of multisource products from which they must select those that are therapeutically equivalent. This phenomenal growth of the generic pharmaceutical industry and the abundance of multisource products have prompted some questions among many health professionals and scientists regarding the therapeutic equivalency of these products, particularly those in certain critical therapeutic categories such as anticonvulsants and cardiovasculars (1, 3-5). Inherent in the currently accepted guidelines for product substitution is the assumption that a generic drug considered to be bioequivalent to a brand-name drug will elicit the same clinical effect. As straightforward as this statement regarding bioequivalence appears to be, it has generated a great deal of controversy among scientists and professionals in the health care field. Numerous papers in the literature indicate that there is concern that the current standards for approval of generic drugs may not always ensure therapeutic equivalence (6-18). The availability of different formulations of the same drug substance given at the same strength and in the same dosage form poses a special challenge to health care professionals, making these issues very relevant to pharmacists in all practice settings. Since pharmacists play an important role in product-selection decisions, they must have an understanding of the principles and concepts of bioavailability and bioequivalence.
8.1.1
RELATIVE AND ABSOLUTE BIOAVAILABILITY

Bioavailability is a pharmacokinetic term that describes the rate and extent to which the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action. Since pharmacologic response is generally related to the concentration of drug at the receptor site, the availability of a drug from a dosage form is a critical element of a drug products clinical efficacy. However, drug concentrations usually cannot be readily measured directly at the site of
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action. Therefore, most bioavailability studies involve the determination of drug concentration in the blood or urine. This is based on the premise that the drug at the site of action is in equilibrium with drug in the blood. It is therefore possible to obtain an indirect measure of drug response by monitoring drug levels in the blood or urine. Thus, bioavailability is concerned with how quickly and how much of a drug appears in the blood after a specific dose is administered. The bioavailability of a drug product often determines the therapeutic efficacy of that product since it affects the onset, intensity and duration of therapeutic response of the drug. In most cases one is concerned with the extent of absorption of drug, (that is, the fraction of the dose that actually reaches the bloodstream) since this represents the "effective dose" of a drug. This is generally less than the amount of drug actually administered in the dosage form. In come cases, notably those where acute conditions are being treated, one is also concerned with the rate of absorption of a drug, since rapid onset of pharmacologic action is desired. Conversely, these are instances where a slower rate of absorption is desired, either to avoid adverse effects or to produce a prolonged duration of action. "Absolute" bioavailability, F, is the fraction of an administered dose which actually reaches the systemic circulation, and ranges from F = 0 (no drug absorption) to F = 1 (complete drug absorption). Since the total amount of drug reaching the systemic circulation is directly proportional to the area under the plasma drug concentration as a function of time curve (AUC), F is determined by comparing the respective AUCs of the test product and the same dose of drug administered intravenously. The intravenous route is the reference standard since the dose is, by definition, completely available. AUC ev F = ---------------AUC iv
(EQ 8-1)
(where AUCEV and AUCIV are, respectively, the area under the plasma concentration-time curve following the extravascular and intravenous administration of a given dose of drug. Knowledge of F is needed to determine an appropriate oral dose of a drug relative to an IV dose. "Relative" or Comparative bioavailability refers to the availability of a drug product as compared to another dosage form or product of the same drug given in the same dose. These measurements determine the effects of formulation differences on drug absorption. The relative bioavailability of product A compared to product B, both products containing the same dose of the same drug, is obtained by comparing their respective AUCs. AUC A RelativeBioavailabilty = -------------AUC B
Copyright 1996 Michael C. Makoid All Rights Reserved (EQ 8-2)
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where drug product B is the reference standard. When the bioavailability of a generic product is considered, it is usually the relative bioavailability that is referred to. A more general form of the equation results from considering the possibility of different doses, AUC Generic ---------------------------Dose Generic ComparativeBioavailability = ----------------------------AUC Brand ------------------------Dose Brand
(EQ 8-3)
The difference between absolute and relative bioavailability is illustrated by the following hypothetical example. Assume that an intravenous injection (Product A) and two oral dosage forms (Product B and Product C), all containing the same dose of the same drug, are given to a group of subjects in a crossover study. Furthermore, suppose each product gave the values for AUC indicated in Table 8-1 on page 4.
TABLE 8-1. Data
for Absolute and Relative Bioavailability

Area Under the Curve (mcg/ml) x hr
Drug Product
A Intravenous injection B Oral dosage form, brand or reference standard C Oral dosage form, generic Product
100 50 40
The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respectively. However, when the two oral products are compared, the relative bioavailability of Product C as compared to Product B is 80%.
8.1.2
FACTORS INFLUENCING BIOAVAILABILITY

Before the therapeutic effect of an orally administered drug can be realized, the drug must be absorbed. The systemic absorption of an orally administered drug in a solid dosage form is comprised of three distinct steps:
1. 2. 3.
disintegration of the drug product dissolution of the drug in the fluids at the absorption site transfer of drug molecule across the membrane lining the gastrointestinal tract into the systemic circulation.
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Any factor that affects any of these three steps can alter the drugs bioavailability and thereby its therapeutic effect. While there are more than three dozen of these factors that have been identified (19-38), the more significant ones are summarized here. The various factors that can influence the bioavailability of a drug can be broadly classified as dosage form-related or patient-related. Some of these factors are listed in Table 8-2 on page 5 and Table 8-3 on page 5, respectively.
TABLE 8-2. Bioavailability
Factors related to the dosage form

Formulation and manufacturing variables Amount of disintegrant Amount of lubricant Special coatings Nature of diluent Compression force
Physicochemical properties of the drug Particle size Crystalline structure Degree of hydration of crystal Salt or ester form
Factors Related to the patient
Physiologic factors Variations in absorption power along GI tract Variations in pH of GI fluids Gastric emptying rate Intestinal motility Perfusion of GI tract Presystemic and first-pass metabolism Age, sex, weight Disease states
Interactions with other substances Food Fluid volume Other drugs
The physical and chemical characteristics of a drug as well as its formulation are of prime importance in bioavailability because they can affect not only the absorption characteristics of the drug but also its stability. Since a drug must be dissolved to be absorbed, its rate of dissolution from a given product must influence its rate of absorption. This is particularly the case for sparingly soluble drugs. All the factors listed in Table 8-2 on page 5 can alter the dissolution rate of the drug, its bioavailability, and ultimately, its therapeutic performance. One of the more important factors that affects the dissolution rate of slowly dissolving substances is the surface area of the dissolving solid (39). Peak blood levels occurred much faster with the smaller particles than the larger ones, primarily
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as a result of their faster dissolution rate. Particle size can also have a significant effect on AUC(40). Serum levels of phenytoin after administration of equal doses containing micronized (formulation G) and conventional (formulation F) drug were measured. Based on the AUC, almost twice as much phenytoin was absorbed after the micronized preparation (40). There are numerous reports of the effects of formulation and processing variables on the dissolution of active ingredients from drug products; an apparently inert ingredient may affect drug absorption. For example, magnesium stearate, a lubricant, commonly used in tablet and capsule formulations, is water-insoluble and water-repellent. Its hydrophobic nature tends to retard drug dissolution by preventing contact between the solid drug and the aqueous GI fluids. Thus, increasing the amount of magnesium stearate in the formulation results in a slower dissolution rate of the drug, and decreased bioavailability(34) . The nature of the dosage form itself may have an effect on drug absorption characteristics. The major pharmaceutical dosage forms for oral use are listed in Table 84 on page 6 in order of decreasing bioavailability of their active ingredients. The decreasing bioavailability is related to the number of steps involved in the absorption process following administration. The greater the number of steps a product must undergo before the final absorption step, the slower is the availability and the greater is the potential for bioavailability differences to occur. Thus, solutions (elixirs, syrups, or simple solutions) generally result in faster and more complete absorption of drug, since a dissolution step is not required. Enteric-coated tablets, on the other hand, do not even begin to release the drug until the tablets empty from the stomach, resulting in poor and erratic bioavailability.
and oral Dosage Forms
Fastest availability
Solutions Suspensions Capsules Tablets Coated tablets
Slowest availability
Controlled-release formulations
Bioavailability studies with pentobarbital from various dosage forms show the absorption rate of pentobarbital after administration in various oral dosage forms decreased in the following order: aqueous solution > aqueous suspension of the free acid > capsule of the sodium salt > tablet of the free acid (41). In addition to the dosage form-related factors identified above, bioavailability may also be affected by a variety of physiologic and clinical factors related to the patient (Table 8-3 on page 5). Considerable inter-subject differences in the bioBasic Pharmacokinetics
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availability of some drugs have been observed. These can often be attributed to individual variations in such factors as GI motility, disease state and concomitantly-administered food or drugs. One example of the myriad of physiologic factors that can affect the bioavailability of an orally-administered drug is a patients gastric emptying rate. Since the proximal small intestine is the optimum site for drug absorption, a change in the stomach emptying rate is likely to alter the rate, and possibly the extent, of drug absorption. Any factor that slows the gastric emptying rate may thus prolong the onset time for drug action and reduce the therapeutic efficacy of drugs that are primarily absorbed from the small intestine. In addition, a delay in gastric emptying could result in extensive decomposition and reduced bioavailability of drugs that are unstable in the acidic media of the stomach (e.g. penicillins and erythromycin). Differences in stomach emptying among individuals have been implicated as a major cause of variations in the bioavailability of some drugs, particularly those with acid-resistant enteric coatings. In a study (42), after the administration of 1.5 g acetaminophen to 14 patients, the maximum plasma concentration ranged from 7.4 to 37 mcg/ml, and the time to reach the maximum concentration ranged from 30 to 180 minutes. Both these parameters of bioavailability were linearly related to the gastric emptying half-life found in each patient. There are numerous factors that affect gastric emptying rate (Table 8-5 on page 8) (43). Factors such as a patients emotional state, certain drugs, type of food ingested and even a patients posture can alter the time course and extent of drug absorption.
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TABLE 8-5.
Factors influencing Gastric Emptying Rate
FACTOR Increased viscosity of stomach contents Body position lying on left side Emotional state stress depression anxiety Activity, exercise Type of meal fatty acids, fats carbohydrates amino acids pH of stomach contents decreased increased Disease states gastric ulcers Crohns disease hypothyroidism hyperthyroidism Drugs atropine propantheline narcotic analgesics amitriptyline metoclopramide decreased decreased decreased decreased increased decreased decreased decreased increased decreased increased decreased decreased decreased decreased decreased
INFLUENCE ON GASTRIC EMPTYING RATE
increased or decreased decreased increased decreased
Since drugs are generally administered to patients who are ill, it is important to consider the effects of the disease process on the bioavailability of the drug. Disease states, particularly those involving the GI tract, such as celiac disease, Crohns disease, achlorhydria, and hypermotility syndromes can certainly alter the absorption of a drug (32). In addition, some diseases concerning the cardiovascular system and the liver may also alter circulating drug levels after oral dosing. Drugs are frequently taken with food, and patients often use mealtimes to remind them to take their medications. However, food can have a significant effect on the bioavailability of drugs. The influence of food on drug absorption has been recog-
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nized for some time, and several reviews have been published on the influence of food on drug bioavailability (30-32, 36, 44). Food may influence drug absorption indirectly, through physiological changes in the GI tract produced by the food, and/or directly, through physical or chemical interactions between the drug molecules and food components. When food is ingested, stomach emptying is delayed, gastric secretions are increased, stomach pH is altered, and splanchnic blood flow may increase. These may all affect bioavailability of drugs. Food may also interact directly with drugs, either chemically (e.g. chelation) or physically, by adsorbing the drug or acting as a barrier to absorption. In general, gastrointestinal absorption of drugs is favored by an empty stomach, but the nature of drug-food interactions is complex and unpredictable; drug absorption may be reduced, delayed, enhanced or unaffected by the presence of food. Table 8-6 on page 9 summarizes some of the studies that have indicated the effect of food on the bioavailability of a variety of drugs.
TABLE 8-6.
Effect of Food on Drug Absorption
Reduced Absorption Ampicillin Aspirin Atenolol Captopril Erythromycin Ethanol Hydrochlorothiazide Penicillins Tetracyclines (most) Source: Ref. 32
Delayed Absorption Acetaminophen Aspirin Cephalosporins (most) Diclofenac Digoxin Furosemide Nitrofurantoin Sulfadiazine Sulfisoxazole
Increased Absorption Chlorothiazide Diazepam Griseofulvin Hydralazine Labetalol Metoprolol Nitrofurantoin Propranolol Riboflavin
The effect of food and type of diet on the bioavailability of erythromycin is shown in a study by Welling (45). The absorption of the antibiotic is significantly reduced when it is administered with food compared with its absorption under fasting conditions. This reduced absorption is primarily a result of degradation of the acid-labile erythromycin due to prolonged retention in the stomach. Delayed absorption due to food has been demonstrated in the case of cephradine in a study by Mischler (46). Similar results have been observed with other oral cephalosporins. Some drugs demonstrate enhanced bioavailability in the presence of food. This has been attributed to a variety of factors, including improved compound solubility and more time for dissolution because of delayed gastric emptying. In the case of
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highly metabolized agents, such as propranolol and metoprolol, the enhanced availability may be due to increased splanchnic blood flow causing reduced first-pass clearance. The circulating levels of these drugs dosed under fasting and non-fasting conditions have been presented in a study by Melander (47). The volume of fluid with which an orally administered dose is taken can also affect a drugs bioavailability. Drug administration with a larger fluid volume will generally improve its dissolution characteristics and may also result in more rapid stomach emptying. Thus, more efficient and more reliable drug absorption can be expected when an oral dosage form is administered with a larger volume of fluid. (45) . Interactions between drugs can have a significant effect on the bioavailability of one or both drugs. Such interactions may be direct, as in chelation of tetracycline by polyvalent metal ions in antacids or the adsorption of digoxin by cholestyramine resin, or indirect, as with the increased rate of acetaminophen absorption due to the increased gastric emptying rate produced by metoclopramide. Most of the reported drug-drug interactions have resulted in a reduction in the rate and/or extent of drug absorption, the most frequent causes being complexing of a drug with other substances, reduced GI motility and alterations in drug ionization (24, 30, 32, 48, 49). Table 8-7 on page 10 summarizes the major mechanisms of GI drug interactions affecting bioavailability.
TABLE 8-7.
Drug interactions affecting absorption
1. Change in gastric or intestinal pH 2. Change in gastrointestinal motility 3. Change in gastrointestinal perfusion 4. Interference with mucosal function (drug-induced malabsorption syndromes) 5. Chelation 6. Exchange resin binding 7. Aadsorption 8. Solution in poorly absorbable liquid
Source: Ref. 23
An example of a direct interaction between drugs affecting bioavailability is the interaction between iron and tetracycline. This is a well-documented and clinically significant interaction which can result in a dramatic reduction in serum concentration of tetracycline (50). The above potential sources of alteration in a drugs bioavailability must be kept in mind when attempting to evaluate the relative performance of drug products on the
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basis of studies performed with healthy human volunteers. These studies are generally performed under tightly-controlled fasting conditions in the absence of other drugs. In practice, however, drugs are seldom taken under such ideal conditions, and the factors leading to changes in drug absorption must be taken into consideration.
8.1.3
METHODS OF ASSESSING BIOAVAILABILITY

Bioavailability testing is a means of predicting the clinical efficacy of a drug; the estimation of the bioavailability of a drug in a given dosage form is direct evidence of the efficiency with which a dosage form performs its intended therapeutic function. The bioavailability of a drug substance formulated into a pharmaceutical product is fundamental to the goals of dosage form design and essential for the clinical efficacy of the medication. Thus, bioavailability testing, which measures the rate and extent of drug absorption, is a way to obtain evidence of the therapeutic utility of a drug product. Bioavailability determinations are performed by drug manufacturers to ensure that a given drug product will get the therapeutic agent to its site of action in an adequate concentration. Bioavailability studies are also carried out to compare the availability of a drug substance from different dosage forms or from the same dosage form produced by different manufacturers.
In-vivo methods
One method for assessing the bioavailability of a drug product is through the demonstration of a clinically significant effect. However, such clinical studies are complex, expensive, time-consuming and require a sensitive and quantitative measure of the desired response. Further, response is often quite variable, requiring a large test population. Practical considerations, therefore, preclude the use of this method except in initial stages of development while proving the efficacy of a new chemical entity. Quantification of pharmacologic effect is another possible way to assess a drugs bioavailability. This method is based on the assumption that a given intensity of response is associated with a particular drug concentration at the site of action; e.g., variation of miotic response intensity can be directly related to the oral dose of chlorpromazine. However, monitoring of pharmacologic data is often difficult, precision and reproducibility are difficult to establish, and there are only a limited number of pharmacologic effects (e.g. heart rate, body temperature, blood sugar levels) that are applicable to this method. Because of these limitations, alternative methods have been developed to predict the therapeutic potential of a drug. The current method to assess the clinical performance of a drug involves measurement of the drug concentrations in the blood
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or urine. In such studies a single dose of the drug product is administered to a panel of normal, healthy adult (18- to 35-year old) subjects. Blood and/or urine samples are collected over a period of time following administration and are analyzed for drug content. Based on the blood concentration as a function of time and/or urinary excretion profile, inferences are drawn regarding the rate and extent of absorption of the drug. These studies are relatively easy to conduct and require a limited number of subjects.
Blood level studies-
Blood level studies are the most common type of human bioavailability studies, and are based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. By monitoring the concentration in the blood, it is thus possible to obtain an indirect measure of drug response. Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken . The key parameters to note are:
1.
AUC
, The area under the plasma concentration-time curve, The AUC is proportional to the
total amount of drug reaching the systemic circulation, and thus characterizes the extent of absorption.
2.
Cmax , The maximum drug concentration. The maximum concentration of drug in the plasma is a function of both the rate and extent of absorption. Cmax will increase with an increase in the dose, as well as with an increase in the absorption rate. Tmax , The time at which the Cmax occurs. The Tmax reflects the rate of drug absorption, and decreases as the absorption rate increases.
3.
Bioavailability (the rate and extent of drug absorption) is generally assessed by the determination of these three parameters. Since the AUC is representative of, and proportional to, the total amount of drug absorbed into the circulation, it is used to quantitate the extent of drug absorption. The calculation of AUC has been discussed in Chapter 4. A variety of pharmacokinetic methods have been suggested for the calculation of absorption rates (51-56). For clinical purposes, it is generally sufficient to determine Cmax and Tmax. If all other factors are constant, such as the extent of absorption and rate of elimination, then Cmax is proportional to the rate of absorption and Tmax is inversely proportional to the absorption rate. Thus, the faster the absorption of a drug the higher the maximum concentration will be and the less time it will take to reach the maximum concentration.
Urinary Excretion Data -
An alternative bioavailability study measures the cumulative amount of unchanged drug excreted in the urine. These studies involve collection of urine samples and the determination of the total quantity of drug excreted in the urine as a function of
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time. These studies are based on the premise that urinary excretion of the unchanged drug is directly proportional to the plasma concentration of total drug. Thus, the total quantity of drug excreted in the urine is a reflection of the quantity of drug absorbed from the gastrointestinal tract. Consider the following example: two products, A and B, each containing 100 mg of the same drug are administered orally. A total of 80 mg of drug is recovered in the urine from Product A, but only 40 mg is recovered from Product B. This indicates that twice as much drug was absorbed from Product A as from Product B. (The fact that neither product resulted in excretion of the entire dose might be due to the existence of other routes of elimination, e.g. metabolism). This technique of studying bioavailability is most useful for those drugs that are not extensively metabolized prior to urinary elimination. As a rule-of-thumb, determination of bioavailability using urinary excretion data should be conducted only if at least 20% of a dose is excreted unchanged in the urine after an IV dose (56). Other conditions which must be met for this method to give valid results include:
1. 2.
the fraction of drug entering the bloodstream and being excreted intact by the kidneys must remain constant. collection of the urine has to continue until all the drug has been completely excreted (five times the half-life1).
Urinary excretion data are primarily useful for assessing extent of drug absorption, although the time course for the cumulative amount of drug excreted in the urine can also be used to estimate the rate of absorption. In practice, these estimates are subject to a high degree of variability, and are less reliable than those obtained from plasma concentration-time profiles (57). Thus, urinary excretion of drug is not recommended as a substitute for blood concentration data; rather, these studies should be used in conjunction with blood level data for confirmatory purposes.
Single-dose versus Multiple-Dose-
Most bioavailability evaluations are made on the basis of single-dose administration. The argument has been made that single doses are not representative of the actual clinical situation, since in most instances, patients require repeated administration of a drug. When a drug is administered repeatedly at fixed intervals, with the dosing frequency less than five half-lives, drug will accumulate in the body and eventually reach a plateau, or a steady-state At steady-state, the amount of drug eliminated from the body during one dosing interval is equal to the available dose (rate in = rate out); therefore, the area under the curve during a dosing interval at steady-state is equal to the total area under the curve obtained when a single dose is administered. This AUC can therefore be
1.
Half life is defined as the length of time required to lose 50% of the drug in the body, assuming first order elimination.
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used to assess the extent of absorption of the drug, as well as its absolute and relative bioavailability. Multiple-dose administration has several advantages over single-dose bioavailability studies, as well as some limitations. These are summarized in Table 8-8 on page 14 (54, 59).
TABLE 8-8. Multiple
dose vs. single dose studies in bioavailability studies
Advantages: Eliminates the need to extrapolate the plasma concentration profiles to obtain the total AUC after a single dose Eliminates the need for a long wash-out period between doses More closely reflects the actual clinical use of the drug Allows blood levels to be measured at the same concentrations encountered therapeutically Because blood levels tend to be higher than in the single-dose method, quantitative determination is easier and more reliable Saturable pharmacokinetics, if present, can be more readily detected at steady-state Limitations: Requires more time to complete More difficult and costly to conduct (requiring prolonged monitoring of subjects Greater problems with compliance control Greater exposure of subjects to the test drug, increasing the potential for adverse reactions
When a drug obeys linear, first-order kinetics, it is possible to estimate the results that would be obtained during multiple dosing from single-dose studies. Projection is easily made with regard to the extent of absorption, using the AUC following a single dose. Results from bioequivalence studies indicate that conclusions on the extent of absorption as assessed by the AUC can be made equally well on the basis of a single or multiple dose study (60). Assessing the rate of absorption during multiple-dosing from single-dose studies has presented a greater problem. Although a number of single-dose characteristics have been suggested as indicators of rate of absorption during multiple dosing (e.g. percent peak-trough fluctuation and percent peak-trough swing), results of bioequivalence studies indicate that only the plateau time (the time during which the concentration exceeds 75% of the maximum concentration, t 75% Cmax) and the residual concentration at the end of the dose interval produce consistent results in assessing the rate of absorption in single- and multiple-dose studies (54, 61). In the case of drugs exhibiting nonlinear kinetics, establishing a linear relationship between single- and multiple-dose bioavailability data has proven to be a difficult task. Thus, it has been recommended that for drugs with either saturable elimination or a nonlinear first-pass effect, steady-state studies be carried out to assess their bioavailability (62).
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8.1.4
STUDY DESIGN
Bioavailability studies involve the administration of the test dosage form to a panel of subjects, after which blood and/or urine samples are collected and analyzed for drug content. Based on the concentration profile of the drug, a judgement is made regarding the rate and extent of absorption of the drug. Normally, the study is conducted in a group of healthy, male subjects who are of normal height and weight, and range in age from 18 to 35 years (6). Questions have been raised regarding the extent to which such a population reflects the performance of a given drug product in a actual patient population. At first glance, it would seem that bioavailability should be determined in patients actually suffering from the disease for which the drug is intended, or in patients representative of the age and sex of subjects who would be using the drug. However, there are several very good reasons for using healthy volunteers rather than patients. In bioavailability studies, it is assumed that there are no physiologic changes in the subjects during the course of the study. If actual patients were used, this would not be a valid assumption, due to possible changes in the disease state. Another potential problem with using patients is that many patients take more than one drug. This could result in a drug-drug interaction which could influence the bioavailability of the test drug. In addition, diet and fluid volume intake, both of which can influence a drugs bioavailability are more difficult to control in a patient population than in a panel of healthy test subjects. In general, it is more difficult with patients to have a standardized set of conditions which are necessary for a dependable bioavailability study. However, it must be recognized that factors that may affect a drugs performance in a patient population may not be detected in a group of healthy subjects. Thus, it is best to conduct a separate study in patients to determine if the disease, for which the drug is intended to be used, alters the bioavailability of the drug. Other important considerations in the methodology of a bioavailability study are sample size, period of trial, and sampling. For statistical purposes, twelve subjects are considered to be a minimum sample size. Otherwise there will not be enough data to draw valid conclusions (63). The bioavailability testing period should be of a sufficient length of time to ensure that drug absorption has been completed. This length of time is at least three times the half-life of the drug; generally a period of four to five times the half-life is used (63, 64). Blood samples should be taken with sufficient frequency to permit an accurate determination of tmax, Cmax and AUC.
8.1.5
IN-VITRO DISSOLUTION AND BIOAVAILABILITY

Pharmaceutical scientists have for many years been attempting to establish a correlation between some physicochemical property of a dosage form and the biological
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availability of the drug from that dosage form. The term commonly used to describe this relationship is "in-vitro/in-vivo correlation" (65). Specifically, it is felt that if such a correlation could be established, it would be possible to use in-vitro data to predict a drugs in-vivo bioavailability. This would drastically reduce, or in some cases, completely eliminate the need for bioavailability tests. The desirability for this becomes clear when one considers the cost and time involved in bioavailability studies as well as the safety issues involved in administering drugs to healthy subjects or patients. It would certainly be preferable to be able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability studies. This would be possible if in-vitro tests could reliably and accurately predict drug absorption and reflect the in-vivo performance of a drug in humans.
Disintegration Tests-
The early attempts to establish an indicator of drug bioavailability focused on disintegration as the most pertinent in-vitro parameter. The first official disintegration test appeared in the United States Pharmacopeia (USP) in 1950. However, while it is true that a solid dosage form must disintegrate before significant dissolution and absorption can occur, meeting the disintegration test requirement only insures that the dosage form (tablet) will break up into sufficiently small particles in a specified length of time. It does not ensure that the rate of solution of the drug is adequate to produce suitable blood levels of the active ingredient. Therefore, while the test for tablet disintegration is very useful for quality control purposes in manufacturing, it is a poor index of bioavailability. Since a drug must go into solution before it can be absorbed, and since the rate at which a drug dissolves from a dosage form often determines its rate and/or extent of absorption, attention has been directed at the dissolution rate. It is currently considered to be the most sensitive in-vitro parameter most likely to correlate with bioavailability. There are two official USP dissolution methods: Apparatus 1, (basket method), and Apparatus 2 (paddle method). For details of these dissolution tests, the reader is recommended to consult USPXXII/NFXVII (66). Dissolution tests are an extremely valuable tool in ensuring the quality of a drug product. Generally, product-to-product variations are due to formulation factors, such as particle size differences, excessive amounts of lubricant and coatings. These factors are reactive to dissolution testing. Thus, dissolution tests are very effective in discriminating between and within batches of drug product(s). The dissolution test, in addition, can exclude definitively any unacceptable product.
Dissolution Tests-
Official dissolution tests -
Limitations of dissolution tests-
There are, however, problems with in-vitro dissolution testing which should be noted - problems which make correlation with in- vivo availability difficult. The first is related to instrument variance and the absence of a standard method. The tests described in the USP are but a few of the large number of dissolution methods proposed to predict bioavailability. Since the dissolution rate of a dosage form is dependent on the methodology used in the dissolution test, changes in the apparaREV. 97.4.22
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tus, dissolution medium, etc., can dramatically modify the results. Table 8-9 on page 17 lists some of the factors related to the dissolution testing device that can affect the dissolution rate of the drug.
TABLE 8-9.
Device factors affecting dissolution
1. Degree of agitation 2. Size and shape of container 3. Composition of dissolution medium pH ionic strength viscosity surface tension 4. Temperature of dissolution medium 5. Volume of dissolution medium 6. Evaporation 7. Hydrodynamics (flow pattern) Source: Ref. 67
Another significant problem is related to the difference between the in-vitro and in-vivo environments in which dissolution occurs. In-vitro studies are generally carried out under controlled conditions in one, or perhaps two, standardized solvents. The in-vivo environment (the gastrointestinal tract), on the other hand, is a continuously changing, complex environment. There are many variables which can affect the dissolution rate of a drug in the gastrointestinal tract, including pH, enzyme secretions, surface tension, motility, presence of other substances and absorption surfaces (68). Thus, drugs frequently dissolve in the body at rates quite different from those observed in an in-vitro test situation. Most of the official dissolution tests tend to be acceleration dissolution tests which bear limited or no relationship with in-vivo dissolution. Adding to the complexity of correlating dissolution with in-vivo absorption are factors such as drug-drug interactions, age, food effects, health, genetic background, biorhythm and physical activity (32, 69). All these factors may have an effect on the rate and extent of absorption of a drug. Thus, the in-vivo environment is far more complex, variable, and unpredictable than any in-vitro test environment, making in-vitro / in-vivo correlations very difficult. A simple dissolution test in a standardized vehicle cannot reflect the in vivo absorption of a drug across a population (70).
Parameters used-
Proper selection of the in-vitro and in-vivo parameters to be correlated is critical in achieving a meaningful correlation. The in-vitro parameter should be selected that has the greatest effect on the absorption characteristics of the drug (71). There are several approaches to establishing a correlation between the dissolution of a
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drug in in- vitro and the bioavailability of a drug in-vivo. The in-vitro - in-vivo correlative methods used most often are of the single-point type where the dissolution rate (expressed as the percent of drug dissolved in a given time, or the time required for a given percent of the drug to dissolve) is correlated to a certain parameter of the bioavailability. Examples of in-vivo parameters used include Cmax, AUC, time to reach half-maximal plasma concentration, the average plasma concentration after 0.5 or 1 hour, maximum urinary excretion rate, and cumulative percent excreted in urine after a given time (71- 78). According to Wagner, the best in-vitro variable to use is the time for 50 percent of the drug to dissolve, and the best variable from in-vivo data to use is the time for 50 percent of the drug to be absorbed (79). Ideally, one would hope to find a linear relationship between some measurement of the dissolution test and some measurement based on bioavailability studies. Unfortunately, most attempts to accomplish this objective have failed.
8.1.6
IN-VITRO / IN-VIVO CORRELATION STUDIESThere have been many attempts to establish in-vitro / in-vivo correlations for a large variety of drugs. Some of these studies have been summarized by Welling, Banakar, and Abdou (71, 80-82). While there are many published examples of satisfactory correlations between absorption parameters and in-vitro dissolution tests, most studies have resulted in poor, or moderate, in-vitro - in-vivo correlations, often involving agreement with only one of the critical bioavailability parameters. Moreover, the positive correlations that have been found generally apply only to the specific formulation studied. There have been instances where the dissolution rates or various formulations of the same drug have been significantly different, yet little or no difference was observed in their bioavailability parameters (83-85). There have also been cases where a drug has failed to meet compendia dissolution standards but has demonstrated adequate bioavailability (86). Welling states: "To the writers knowledge, there have been no studies that have accurately correlated in- vitro and in-vivo data to the point that the use of upper and lower limits for in-vitro dissolution parameters can be confidently used to predict in-vivo behavior and, therefore, to replace in-vivo testing" (71). Even if an in-vitro test could be designed that would accurately reflect the dissolution process in the gastrointestinal tract, dissolution is only one of many factors that affect a drugs bioavailability. For example, saturable presystemic metabolism may affect the extent of drug absorption, but this would not be predicted by an
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in-vitro test. Dissolution studies also would not predict poor bioavailability due to instability in gastric fluid or complexation with another drug or food component. Thus, the ultimate evaluation a drug products performance under the conditions expected in clinical therapy must be an in-vivo test; a dissolution test is unlikely to entirely replace bioavailability testing (70, 87, 88). In-vitro methods are important in the development and optimization of dosage forms while in-vivo tests are essential in obtaining information on the behavior of medication in living organisms. One cannot be substituted for the other (69).
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8.2 Bioequivalence
Definitions
With the phenomenal increase in the availability of generic drugs in recent years, the issues of bioavailability and bioequivalence have received increasing attention. In order for a drug product to be interchangeable with the pioneer (innovator or brand name) product, it must be both pharmaceutically equivalent and bioequivalent to it. According to the FDA, "pharmaceutical equivalents" are drug products that contain identical active ingredients and are identical in strength or concentration, dosage form, and route of administration (89). However, pharmaceutical equivalents do not necessarily contain the same inactive ingredients; various manufacturers dosage forms may differ in color, flavor, shape, and excipients. The terms "pharmaceutical equivalents" and "chemical equivalents" are often used interchangeably. "Bioequivalence" is a comparison of the bioavailability of two or more drug products. Thus, two products or formulations containing the same active ingredient are bioequivalent if their rates and extents of absorption are the same. When a new formulation of an existing drug is developed, its bioavailability is generally evaluated relative to the standard formulation of the originator. Indeed, a bioequivalence trial against the standard formulation is the key feature of an Abbreviated New Drug Application (ANDA) submitted to the Food and Drug Administration by a manufacturer who wishes to produce a generic drug. For a generic drug to be considered bioequivalent to a pioneer product, there must be no statistical differences (as specified in the accepted criteria) between their plasma concentration-time profiles. Because two products rarely exhibit absolutely identical profiles, some degree of difference must be considered acceptable, as will be discussed later. Since the concentration of a drug in blood is used as an assessment of its clinical performance, inherent in the demonstration that two preparations containing equivalent amounts of the same drug produce similar concentrations of the drug entity in blood is the assumption that they will elicit equivalent drug responses. Thus, two products that are deemed to be bioequivalent are also assumed to be therapeutically equivalent, and therefore interchangeable. This principle is fundamental to the concept of bioequivalence and is the basic premise on which it is founded. In general, the FDA considers two products to be "therapeutic equivalents" if they each meet the following criteria (90):
1. 2.
they are pharmaceutical equivalents, they are bioequivalent (demonstrated either by a bioavailability measurement or an in vitro standard),
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3. 4. 5.
they are in compliance with compendial standards for strength, quality, purity and identity, they are adequately labelled, and they have been manufactured in compliance with Good Manufacturing Practices as established by the FDA.
Background
The first intimations of bioequivalence problems with multi-source drug products were given by early investigations of the availability of vitamins, aspirin, tetracycline, and tolbutamide (91-97). In 1974, after an extensive review of the bioavailability of drugs, Koch-Weser concluded that " . . . among drugs thus far tested bioinequivalence of different drug products has been far more common than bioequivalence" (98). Of particular note were the studies involving digoxin; the findings of these investigations sparked the discussion about bioequivalence assessment that still continues today. Significant differences were seen in the bioavailability of digoxin not only between products supplied by different companies, but also between lots obtained from the same manufacturer (99). Because of the narrow therapeutic range for this drug, and because the drug is utilized in the treatment of cardiac patients, these findings generated a great deal of concern. Similar reports of bioinequivalence and therapeutic inequivalence appeared for other drugs as well, including phenytoin, phenylbutazone, chloramphenicol, tolbutamide and thyroid (6). The clinical significance of these reported differences in bioavailability relates to the therapeutic index of the drug, the dose of the drug and the nature of the disease. In 1973 the Ad Hoc Committee on Drug Product Selection of the American Pharmaceutical Association published a list of drugs with a potential for therapeutic inequivalence based on reported evidence of bioinequivalence (100). The drugs fall in three categories: "high," "moderate," or "low risk" based on the clinical implications (Table 8-10 on page 22).
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TABLE 8-10. Drugs
with various risk potential for inequivalence

Moderate Risk Potential amphetamines (sustained-release) ampicillin chloramphenicol chlorpromazine digitoxin erythromycin griseofulvin oxytetracycline penicillin G (buffered) pentobarbital phenylbutazone phenacetin potassium chloride (solid dosage forms) salicylamide secobarbital sulfadiazine tetracycline tolbutamide Low or Negligible Risk Potential acetaminophen codeine ferrous sulfate hydrochlorothiazide ephedrine isoniazid meprobamate penicillin VK sulfisoxazole
High Risk Potential aminophylline aspirin (when used in high dose levels) bishydroxycoumarin digoxin dipheylhydantoin (phenytoin) para-aminosalicylic acid prednisolone prednisone quinidine warfarin
The concern about the bioinequivalence of some drugs led to the establishment in 1974 of the Drug Bioequivalence Study Panel of the Office of Technology Assessment (OTA). The objective was to ensure that drug products of the same physical and chemical composition would produce similar therapeutic effects. Among the 11 recommendations of the Panel was the conclusion that not all chemical equivalents were interchangeable, but the goal of interchangeability was achievable for most oral drug products (101). The Report recommended that a system should be organized as rapidly as possible to generate an official list of interchangeable drug products. The OTA Report, as well as the growing awareness within the scientific and regulatory communities of bioavailability problems with marketed drug products, focused the attention of the FDA on bioequivalence and bioavailability problems and issues.
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8.2.1
BIOEQUIVALENCE REGULATIONS
In 1977, the FDA implemented a series of bioavailability and bioequivalence regulations which formed the basis of subsequent discussion, if not controversy, of therapeutic equivalency of drug products (102). The regulations are divided into two separate regulations; Subpart B - Procedures for Determining the Bioavailability of Drug Products and Subpart C - Bioequivalence Requirements. While Table 11 summarizes the key provisions of the bioavailability regulations, those for bioequivalence requirements are summarized in Table 8-11 on page 23.
TABLE 8-11. Key
provisions for bioavailabilty regulations
1. Defines bioavailability in terms of both the rate and extent of drug absorption. 2. Describes procedures for determining the bioavailability of drug products. 3. Sets forth requirements for submission of in vivo bioavailability data. 4. Sets forth criteria for waiver of human in vivo bioavailability studies. 5. Provides general guidelines for the conduct of in vivo bioavailability studies. 6. Imposes a requirement for filing an Investigational New Drug Application. Source: Ref. 103
Criteria for establishing a bioequivalence requirement -
The 1977 Bioequivalence regulations set forth the following criteria and evidence supporting the establishment of a bioequivalence requirement for a given drug product:
1. 2. 3.
Evidence from well-controlled clinical trials or controlled observations in patients that such products do not give comparable therapeutic effects. Evidence from well-controlled bioequivalence studies that such products are not bioequivalent drug products. Evidence that the drug products exhibit a narrow therapeutic ratio, (e.g., there is less than a two-fold difference in the median lethal dose (LD50) and median effective dose (ED50) value or have less than a two-fold difference in the minimum toxic concentration and minimum effective concentrations in the blood), and safe and effective use of the drug product requires careful dosage titration and patient monitoring. Competent medical determination that a lack of bioequivalence would have a serious adverse effect in the treatment or prevention of a serious disease or condition. Physicochemical evidence of any of the following:
a. b.
4. 5.
The active drug ingredient has a low solubility in water--e.g., less than 5 mg/ml.
The dissolution rate of one or more such products is slow--e.g., less than 50 percent in thirty minutes when tested with a general method specified by an official compendium or the FDA. The particle size and/or surface area of the active drug ingredient is critical in determining bioavailability.
c.
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d. e.
Polymorphs, solvates, complexes, and such, exist that could contribute to poor dissolution and may affect absorption. There is a high excipient/active drug ratio present in the drug product--e.g., greater than 5 to 1.
f.
The presence of specific inactive ingredients (e.g. hydrophilic or hydrophobic excipients) that either may be required for absorption of the active drug or may interfere with such absorption. The drug is absorbed in large part in a particular segment of the gastrointestinal tract or is absorbed from a localized site. Poor absorption of the drug, even when it is administered as a solution--e.g., less than 50 percent compared to an intravenous dose. The drug undergoes first-pass metabolism in the intestinal wall or liver. The drug is rapidly metabolized or excreted, requiring rapid dissolution and absorption for effectiveness. The drug is unstable in specific portions of the gastrointestinal tract, requiring special coatings and formulations--e.g., enteric coatings, buffers, film coatings--to ensure adequate absorption. The drug follows nonlinear kinetics in or near the therapeutic range, and the rate and extent of absorption are both important to bioequivalence.
6.
Pharmacokinetic evidence of any of the following:

a.
b. c. d. e.
f.
Types of Bioequivalence Requirements
In the event that a drug meets one or more of the above six criteria, a bioequivalence requirement is established. The requirement could be either an in-vivo or an in-vitro investigation, as specified by the FDA. The types of bioequivalence requirements include the following:
1. 2. 3. 4. 5.
An in-vivo test in humans. An in-vivo test in animals that has been correlated with human in- vivo data. An in-vivo test in animals that has not been correlated with human in- vivo data. An in-vitro bioequivalence standard, i.e., an in-vitro test that has been correlated with human in-vivo bioavailability data. A currently available in-vitro test (usually a dissolution rate test) that has not been correlated with human in-vivo bioavailability data.
The regulations state that in-vivo testing in humans would generally be required if there is well-documented evidence that pharmaceutical equivalents intended to be used interchangeably meet one of the first three criteria used to establish a bioequivalence requirement:
1. 2. 3.
The drug products do not give comparable therapeutic effects. The drug products are not bioequivalent. The drug products exhibit a narrow therapeutic ratio (as described above), and safe and effective use of the product requires careful dosage titration and patient monitoring.
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Criteria for waiver of evidence of in-vivo bioavailability -
Although a human in-vivo test is considered to be preferable to other approaches for the most accurate determination of bioequivalence, there is a provision in the 1977 regulations for waiver of an in-vivo bioequivalence study under certain circumstances. For some drug products, the in-vivo bioavailability of the drug may be self-evident or unimportant to the achievement of the products intended purposes. The FDA will waive the requirement for submission of in-vivo evidence of bioavailability or bioequivalence if the drug product meets one of the following criteria:
1.
The drug product is a solution intended solely for intravenous administration, and contains the active drug ingredient in the same solvent and concentration as an intravenous solution that is the subject of an approved full New Drug Application (NDA). The drug product is a topically applied preparation intended for local therapeutic effect. The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid. The drug product is administered by inhalation and contains the active drug ingredient in the same dosage form as a drug product that is the subject of an approved full NDA. The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that contains an active drug ingredient in the same concentration as a drug product that is the subject of an approved full NDA and contains no inactive ingredient that is known to significantly affect absorption of the active drug ingredient. The drug product is a solid oral dosage form (other than enteric-coated or controlled-release) that has been determined to be effective for at least one indication in a Drug Efficacy Study Implementation (DESI) notice and is not included in the FDA list of drugs for which in vivo bioequivalence testing is required. The drug product is a parenteral drug product that is determined to be effective for at least one indication in a DESI notice and shown to be identical in both active and inactive ingredients formulation, with a drug product that is currently approved in an NDA. (Excluded from the waiver provision are parenteral suspensions and sodium phenytoin powder for injection.)
2. 3. 4. 5.
6.
7.
According to the regulations, the bioavailability of certain drug products may be demonstrated by evidence obtained in-vitro in lieu of in-vivo data. Thus, the FDA also permits waiver of the in-vivo requirements if a drug product meets one of the following criteria:
1. 2.
The drug product is one for which only an in-vitro bioequivalence requirement has been approved by the FDA. The drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to another drug product made by the same manufacturer and the following conditions are met:
a. b. c.
the bioavailability of this other product has been demonstrated both drug products meet an appropriate in-vitro test approved by the FDA
the applicant submits evidence showing that both drug products are proportionally similar in their active an inactive ingredients.
3.
The drug product is shown to meet an in-vitro test that assures bioavailability, i.e., an in-vitro test that has been correlated with in-vivo data.
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4.
The drug product is a reformulated product that is identical, except for color, flavor, or preservative, to another drug product made by the same manufacturer, and both of the following conditions are met:
a. b.
the bioavailability of the other product has been demonstrated. both drug products meet an appropriate in vitro test approved by the FDA.
5.
The drug product contains the same active ingredient and is in the same strength and dosage form as a drug product that is the subject of an approved full NDA or Abbreviated New Drug Application (ANDA) and both drug products meet an appropriate in-vitro test that has been approved by the FDA.
Although the above list of criteria for waiver of an in-vivo bioavailability study is quite lengthy, currently virtually all new tablet or capsule formulations from which measurable amounts of drug or metabolites are absorbed into the systemic circulation require a human bioequivalence study for approval (104).
TABLE 8-12. Key
Provisions for bioequivalence requirements
1. Defines procedures for establishing a bioequivalence requirement. 2. Sets forth criteria to establish a bioequivalence requirement. 3. Describes types of bioequivalence requirements. 4. Sets forth requirement for in-vitro batch testing and certification. 5. Describes requirements for marketing a drug product subject to a bioequivalence requirement. 6. Sets forth requirements for in-vivo testing of a drug product not meeting an in-vitro bioequivalence standard. Source: Ref. 103
8.2.2
STUDY DESIGN
A single-dose bioequivalency study is generally performed in normal, healthy, adult volunteers. The subject population should be selected carefully, so that product formulations, and not intersubject variations, will be the only significant determinants of bioequivalence (105). A minimum of 12 subjects is recommended, although 18 to 24 subjects are used to increase the data base for statistical analysis. The test and the reference products are usually administered to the subjects in the fasting state (overnight fast for at least 10 hours, plus 2 to 4 hours after administration of the dose), unless some other approach is more appropriate for valid scientific reasons. These subjects should not take any other medication for one week prior to the study or during the study. The bioavailability is determined by the collection of either blood samples or urine samples over a period of time and measurement of the concentration of drug present in the samples. Generally, a crossover study design is used. Using this method, both the test and the reference products are compared in each subject, so that inter-subject variables,
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such as age, weight, differences in metabolism, etc., are minimized. Each subject thus acts as his own control. Also, with this design, subjects daily variations are distributed equally among all dosage forms or drug products being tested. The subjects are randomly selected for each group and the sequence of drug administration is randomly assigned. The administration of each product is followed by a sufficiently long period of time to ensure complete elimination of the drug (washout period) before the next administration. The washout period should be a minimum of 10 half-lives of the administered drug (106). A waiting period of one week between administration is usually an adequate washout period of most drugs. With a drug requiring a washout period of one week, a typical randomized twoway crossover bioequivalency study is shown in Table 8-13 on page 27.
TABLE 8-13. Two
way cross over design
Treatment Groupa I II
a
Week 1 A B
Week 2 B A
10 subjects per group
Assuming that the in-vivo performances of the two formulations are to be compared by examining their blood level profiles, one must be certain that an adequate number of blood samples are taken. Blood samples should be drawn with sufficient frequency to provide an accurate characterization of the drug concentration-time profile from which tmax, Cmax and AUC can be determined. Typically, a total of 10 to 15 sampling times might be required (107). Moreover, all samples should be taken at the same time for both the test and the reference product to permit proper statistical analysis. Additional features which contribute to good study design include:
1. 2. 3.
All drug samples obtained for the test and reference preparations should be analyzed by the same method. Identical test conditions must be used for the two groups of subjects. For example, the types of foods, fluid intake, physical activity, and posture should all be rigidly controlled in the study. The physical characteristics of the subjects (such as age, height, weight, and health) should be standardized.
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Several important questions have been raised specifically regarding the design of the bioequivalence tests. One of these deals with the selection of the appropriate reference standard, since this is a critical component of a protocol (6, 108). Normally, the reference product is that available from the innovator company holding the New Drug Application. However, in cases where there may be some question as to the bioavailability of such a product, the study may utilize a solution of the drug instead of or in addition to the marketed product. The use of a solution can, of course, result in some difficulty in interpretation of the data: a solid dosage form, when compared to a solution, will usually exhibit a lower Cmax and a longer tmax. The clinical significance of these differences may be difficult to assess. In some instances, the FDA must designate a specific product as the reference standard from among two or more possible products; e.g., Proventil tablets, 4 mg (Schering), not Ventolin tablets 4 mg (Allen and Hanburys), is the reference product in bioequivalence studies of albuterol sulfate conventional tablets (108).
Advantages of Multipledose vs. single dose studies:
Another important question is whether the bioequivalence trial should compare single doses of the formulations or if it should compare "steady-state" conditions reached after multiple dosing. It would seem that multiple dosing would be the logical choice for drugs intended for long-term use since this would give a more realistic comparison in view of the way in which the drug is normally administered. Other advantages of conducting a multiple-dose study over a single-dose study include (54, 59):
1. 2. 3.
Multiple-dosing eliminates the long washout periods required between single-dose administrations. The switch-over from one formulation to the other can take place in steady state. Single-dose studies may pose problems of sufficiently long sampling periods in order to get reliable estimates of terminal half-life, which is needed for correct calculation of the total AUC. Multiple-dose studies yield higher concentrations of drug in the blood, making accurate measurement easier. In addition, since drug concentrations need to be measured only over a single dosing interval at steady state, the need to measure lower concentrations during a disposition phase is avoided. Multiple-dosing studies can be conducted in patients, rather than healthy volunteers, allowing the use of higher doses. Usually, smaller intersubject variability is observed in steady-state studies, which may permit the use of fewer subjects. Nonlinear pharmacokinetics, if present, can be more readily detected at steady-state following multiple-dosing.
4. 5. 6.
Thus, for some drug products, multiple-dose bioequivalence studies are appropriate and should be performed. In fact, according to one of the conclusions of the Bio- International '92 conference on the bioequivalence of highly variable drugs, a multiple-dose study is required in the case of compounds exhibiting nonlinear pharmacokinetics (110). The circumstances under which a multiple-dose study may be required are summarized in the regulations (109):
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1. 2. 3. 4.
When there is a difference in the rate of absorption but not in the extent of absorption. When there is excessive variability in bioavailability from subject to subject. When the concentration of the active moiety in the blood resulting from a single dose is too low for accurate determination. When the drug product is a controlled-release dosage form.
On the other hand, multiple-dose bioequivalence studies are undesirable in some respects. Healthy subjects should not be dosed with any drug for an extended period of time (59). Multiple-dose studies are also generally more difficult to carry out, especially with regard to ensuring subject compliance with dosing and dietary restrictions. Therefore, most bioequivalence studies are conducted as single-dose studies. Multiple-dose studies should be performed only when a single-dose study is not a reliable indicator of bioavailability (111).
8.2.3
ASSESSMENT OF BIOEQUIVALENCE
In order for different formulations of the same drug substance to be considered bioequivalent, they must be equivalent with respect to the rate and extent of drug absorption. Thus, the two predominant issues involved in the assessment of bioequivalence are: the pharmacokinetic parameters that best characterize the rate and extent of absorption and, the most appropriate method of statistical analysis of the data.
Pharmacokinetic criteria
With regard to the choice of the appropriate pharmacokinetic characteristics, Westlake suggests comparisons of the formulations should be made with respect to only those parameter(s) of the blood level profile that possess some meaningful relation to the therapeutic effect of the drug (107). Since the AUC is directly proportional to the amount of drug absorbed, this pharmacokinetic parameter is most commonly used to characterize the extent of absorption, both in single- and multiple- dose studies. The choice of an appropriate pharmacokinetic characteristic for the rate of absorption is still being discussed with considerable controversy (112, 113). Although a broad array of methods exists for calculating absorption rates (e.g. moment analysis, deconvolution procedures and curve-fitting), the most commonly used parameters are peak concentration (Cmax) and time to peak concentration (tmax). Although these parameters have been observed to have significant variances and may be difficult to determine accurately, they remain the parameters generally requested as rate characteristic by most regulatory authorities for immediate-release products (112).
Statistical criteria
After a bioequivalence study is conducted and the appropriate parameters are determined, the pharmacokinetic data must be examined according to a set of predetermined criteria to confirm or refute the bioequivalency of the test and referREV. 97.4.22
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ence formulations. That is, one must determine whether the test and reference products differ within a predefined level of statistical significance. Since the statistical outcome of a bioequivalence study is the primary basis of the decision for or against therapeutic equivalence of two products, it is critically important that the experimental data be analyzed by an appropriate statistical test. In the early 1970s, bioequivalence was usually determined only on the basis of mean data. Mean AUC and Cmax values for the generic product had to be within +20% of those of the reference (innovator) product (108). Although the 20% value was somewhat arbitrary, it was felt that for most drugs, a 20% change in the dose would not result in significant differences in the clinical response to drugs (114). A relatively common misconception is that current regulatory standards still allow this difference of 20% in the means of the pharmacokinetic variables (Cmax and AUC) of the test and reference formulations. The FDAs statistical criteria for approval of generic drugs now requires the application of confidence limits to the mean data, using an analysis known as the two one-sided tests procedure (115). This change came about as a result of the conclusion of the FDA Bioequivalence Task Force in 1986 that the use of a 90% confidence interval based on the two one-sided t-tests approach was the best available method for evaluating bioequivalence (111). Westlake was the first to suggest the use of confidence intervals as a means of testing for bioequivalence (116). Recognizing that no two products will result in identical blood-level profiles, and that there will be differences in mean values between products, Westlake pointed out that the critical issue was to determine how large those differences could be before doubts as to therapeutic equivalence arose (107, 117). A test formulation was considered to be bioequivalent to a reference formuCp max test AUC test - < 1.2 . (119). By this procedure, lation if 0.8 < ------------------- < 1.2 and 0.8 < ------------------AUC ref Cp max ref if test and reference products were not bioequivalent (i.e. means differed by more than 20%), there was a 5% chance of concluding that they are bioequivalent. The current FDA guidelines are that two formulations whose rate and extent of absorption differ by -20%/+25% or less are generally considered bioequivalent (90). In order to verify that the -20%/+25% rule is satisfied, the two one-sided statistical tests are carried out: one test verifies that the bioavailability of the test product is not too low and the other to show that it is not too high. The current practice is to carry out the two one-sided tests at the 0.05 level of significance. Computationally, the two one-sided tests are carried out by computing a 90% confidence interval. For approval of an ANDA, a generic manufacturer must show that the 90% confidence interval for the ratio of the mean response (usually AUC
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and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25. Since these tests are carried out at the 0.05 level of significance, there is no more than a 5% chance that they will be approved as equivalent if they differ by as much or more than is allowed by the equivalence criteria (-20%/+25%). Since this test requires that the 90% confidence interval of the difference between the means be within a range of -20%/+25%, it is more stringent than simply requiring the comparison of the test and reference products AUC and Cmax to be within the 80 to 125% range. If the mean response of the generic product in the study population is near 20% below or 25% above the innovator mean, one or both of the confidence limits will fall outside the acceptable range and the product will fail the bioequivalence test. Thus, the confidence interval requirement ensures that the difference in mean values for AUC and Cmax will actually be less than -20%/ +25%. It should be pointed out that the standards vary among drugs and drug classes. For example, antipsychotic agents may fall within a 30% variation and antiarrhythmic agents may be allowed a 25% variation (122). The actual differences between brand and generic products observed in bioequivalence studies have been reported to be small. The FDA has stated that for post-1962 drugs approved over a two-year period under the Waxman-Hatch bill (1984), the mean bioavailability difference between the generic and pioneer products has been about 3.5% (120). In addition, 80% of the generic drugs approved by the FDA between 1984 and 1986 differed from the innovator products by an observed difference of only +5%. Such differences are small when compared to other variables of drug therapy and would not be expected to produce clinically observable differences in patient response.
8.2.4
CONTROVERSIES AND CONCERNS IN BIOEQUIVALENCE

The design, performance and evaluation of bioequivalence studies have received a great deal of attention over the past decade from academia, the pharmaceutical industry and regulatory agencies. A number of concerns and questions have been raised about the conduct of bioequivalence studies as well as the guidelines and criteria used to determine bioequivalence (112). Many of these concerns were triggered by the passage of the Drug Price Competition and Patent Term Restoration Act (The Waxman-Hatch Amendments) by Congress in 1984. This Act provided for an expedited approval by the FDA of generic drugs, thereby expanding the potential generic market for prescription generic drugs (121). Shortly after the passage of this Act, numerous published reports appeared in the scientific literature questioning the FDAs ability to ensure that generic drugs were equivalent to the brand name drugs they were copying. Most of the concerns of the scientific community centered around adequate standards for evaluation of bioequivalence
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and correlation between bioequivalence and therapeutic equivalence. Some of the issues and concerns that were raised are summarized in Table 8-14 on page 32 (8, 13).
TABLE 8-14. Issues
and Concerns regarding bioequivalence
Correct analysis of drugs in biological fluids Appropriate choice of pharmacokinetic parameters to assess bioequivalence Generalizing results obtained in healthy volunteers to patients Problems involved in extrapolating from single-dose studies to steady-state Importance of evaluating active metabolites Inadequate statistical criteria to evaluate bioequivalency Bioequivalence does not always ensure therapeutic equivalence Lack of clear guidelines for evaluation of bioequivalence
At the center of the controversy were the methods and criteria used by the FDA to determine bioequivalence. Assessment of bioequivalence was done on the basis of mean data: mean AUC and Cmax values for the generic product had to be within +20% of those of the innovator product for approval. A statistical test was employed to assess the power of the test to detect a 20% mean difference in treatments. For drugs that could not meet the statistical criteria because of inherent variability, another rule was used, the so-called "75/75" rule: that in at least 75% of the subjects, the test formulation must fall within the range of 75% to 125% of the reference standard to be considered equivalent (122). It was felt by many that these rules permitted too much variability in the bioavailability of test drugs and could result in therapeutic failure or increased risk of side effects (4, 15, 123). Statistically, the power approach and the 75/75 rule were shown to have poor performance characteristics and bioequivalence evaluation based on these methods was discontinued by the FDA in 1986. In their place, the Agency currently employs the two one-sided tests procedure, as previously discussed. Although the decision of bioequivalence is now made in a more statistically valid way and the associated concerns have diminished somewhat, some important questions and controversies in bioequivalence remain. These are primarily centered around study design, the criteria used to establish or refute equivalence, and the assumption that products that are bioequivalent are therapeutically equivalent. One criticism of bioequivalence testing is that it is almost always done in a panel of young, healthy male volunteers rather than in the target population for which the drug is intended. Clearly, the performance of a drug product in a 20-year-old male will not be the same as in an 85-year-old woman. Serious concerns have been
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raised that different results would be observed in elderly patients, in women, in patients with diseases of the gastrointestinal tract, and in patients with diminished renal or hepatic function. However, although factors such as age and disease state might affect the actual observed concentrations of drug, the products being compared should be affected in a similar fashion, and one can still be compared to the other. If two products show an equivalent level in healthy volunteers, their levels should be elevated to the same extent in patients with impaired hepatic function. Thus, they can still be compared to each other. Healthy male volunteers are generally used in bioequivalence studies to assure a homogeneous study population and to permit focus on formulation factors that might affect bioavailability. In addition, healthy subjects are more likely to remain stable during the study. The condition of actual patients might change due to the disease resulting in greater variability in the data. The FDA does recognize the possibility that some conditions could cause two products that are bioequivalent in healthy subjects to be bioinequivalent in certain patients and is prepared to modify its guidelines if necessary. A study design-related area of concern is average versus individual bioavailability. Current procedures assess equivalence in terms of average bioavailabilities, and do not address within-subject equivalence. In recent years, there has been increased interest expressed in the variability of response, particularly variability within an individual. This has given rise to the most recent controversy in bioequivalence assessment, namely whether average bioequivalence is adequate to allow interchangeability of drugs in an individual (112). Anderson and Hauck believe that a different, more stringent, notion of bioequivalence, referred to as individual bioequivalence, is needed to provide assurance that an individual patient can be switched from one formulation to another (124). The second major area of controversy has focused on the criteria used to determine bioequivalence. Implicit in the FDA guidelines is the assumption that a -20%/ +25% change in mean serum concentration of drugs can be safely tolerated. However, there is little documentation demonstrating whether 20% variation in bioavailabilities does or does not affect the safety and efficacy of drugs. There are certain critical therapeutic categories (Table 8-15 on page 34) in which minor fluctuations in blood levels may have a substantial impact on therapeutic outcome or toxicity (125, 126). In view of this, some scientists believe that the FDA should be more stringent, requiring the mean values for AUC to be within 10% rather than 20%/25%. The Bioequivalence Task Force, in its 1988 report, concluded that for certain drugs or drug classes, there is clinical evidence that may indicate a need for tighter limits than the then-generally applied +20% rule (111). The Task Force recommended that the Agency consider using as an "additional nonstatistical criterion" a mean difference in AUC of +10%; however, this additional criterion would not be essential to ensuring drug bioequivalence.
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TABLE 8-15.
Critical Therapeutic Catagories of Drugs
Category Cardiovascular drugs Anticonvulsants Bronchodilating agents Oral anticoagulants
Example digoxin phenytoin theophylline warfarin
In general, the choice of the appropriate bioequivalence range should be done on clinical grounds; for a drug with a narrow therapeutic range, more stringent limits should be considered. On the other hand, the current requirements for Cmax for some drugs may be too stringent, considering the difficulty in accurately estimating this value. For example, it has been suggested that the acceptable bioequivalence range for Cmax for fast-releasing nifedipine formulations should be 70% to 130%, rather than the usual 80% to 125%. In light of this, many, including the Pharmaceutical Research and Manufacturers of America (formerly the Pharmaceutical Manufacturers Association [PMA]), feel that the FDA should repudiate its -20%/+25% rule and develop drug-by- drug bioequivalence criteria (127). A third source of controversy in bioequivalence is the very foundation on which the whole concept of bioequivalence is based: the central assumption is that if two products are shown to be bioequivalent by currently accepted standards, then they are also therapeutically equivalent, and thus interchangeable. A number of critics have challenged this "bioequivalence = therapeutic equivalence" equation, pointing out that this relationship has not been conclusively established for most drugs (9, 13, 16, 128). These terms are, in fact, not interchangeable; bioequivalence means that two products have basically superimposable blood level curves (within specified limits) while therapeutic equivalence means the products produce similar effects. There may be situations where two products have similar blood concentrations, yet if the drug has a narrow therapeutic range, they may have significantly different therapeutic effects. On the other hand, there may be products which have widely varying blood level profiles, but exhibit very little difference in their clinical effect. This might be the case for drugs with a wide therapeutic range. In addition, the therapeutic efficacy of some drugs is not necessarily related to their blood levels, e.g., some psychoactive drugs, where the end point of drug effects is psychological and behavioral response (129).
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Williams suggests several ways that the integrity of a bioequivalence study as a prediction of therapeutic equivalence could be assessed (104). One way involves the performance of specific clinical studies to confirm that products shown to be bioequivalent in healthy subjects would be bioequivalent in the patient population as well. A second way suggested is through post-marketing surveillance of therapeutic response produced by different formulations of the same drug under actual conditions of use. A third method is based on anecdotal reports. Williams points out that none of these methods have been systematically employed to confirm current bioequivalence methodology. Thus, a number of problems remain in the bioequivalence process which should be addressed. FDA scientists themselves have readily acknowledged the existence of shortcomings in the bioequivalence testing program. However, a great deal of progress has been made in this area in the last twenty years. The improved design of the studies, the interpretation of the data, the increased scientific rigor of the acceptance criteria, as well as the more rigorous auditing and inspection program have made bioequivalence data an appropriate and valid means of approving generic drug products.
8.2.5
GENERIC DRUGS AND PRODUCT SELECTION

Generic drug utilization has increased dramatically in the last 20 years. In 1975, approximately 9% of all prescription drugs dispensed were generic versions (130). This percentage rose to 20% in 1984, and 40% in 1991. It has been variously estimated that the generic share of all new prescriptions will be 46% to 65% in 1995 (131-133). This rise of generics has not gone altogether smoothly, however; the popularity of generic drugs took a sharp downturn in 1989 when scandal rocked the generic drug industry. This involved illegal and unethical acts by some generic drug companies -- payoffs to FDA employees and fraudulent drug-approval test -- aimed at getting drugs approved ahead of other firms (134-138). Although these events did shake the confidence of pharmacists, physicians and the public in the quality of generic drugs and cast a shadow over generics generally, these concerns were relatively short-lived. Numerous surveys conducted one to two years after the scandal unfolded indicated that confidence in generic drugs had been regained and that the generic industry was in better shape with pharmacists than it had been before the scandal occurred (139-146). Given the seriousness of the events, the speed with which generics came back was impressive. This was due in part to the FDAs reaction to the scandal: a multilevel reorganization of its generic drug operations and a comprehensive inspection of the leading manufac-
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turers of generic drugs (134, 140, 147, 148). It was felt that this stringent FDA review of generics proved the overall integrity of the companies that emerged with a clean bill of health. After a sharp drop in the use of generic drugs in 1989, they began to rise nearly as quickly as they fell, and by mid-1990, sales of generics were approaching their previous record high (141). This trend in generic drug utilization is expected to continue its upward spiral, with newly generic drugs coming to market at an increasing rate. There are several factors that have contributed to this period of considerable growth in the generic drug industry. One major factor was the passage of the Drug Price Competition and Patent Term Restoration Act (Waxman-Hatch Act) in 1984. This act, by eliminating the requirement for clinical safety and efficacy testing for generics of drugs introduced after 1962, greatly expedited the entry of generic drugs into the marketplace. The purpose of this act was to facilitate generic competition and thereby reduce health care costs. This act significantly expanded the number of drugs eligible to be manufactured as generics. Another factor fueling the surge of generic products is the abundance of brand name drugs whose patents began expiring in 1986. Between 1991 and 1994, patents expired on brand-name drugs whose combined annual sales totaled $10 billion (141). These include Procardia, Ceclor, Tagamet, Cardizem, Feldene, Naprosyn, and Xanax. All told, more than 100 drugs worth upwards of $25 billion in sales will have come off patent by the year 2000 (149). Table 8-16 on page 37 lists some recent and impending patent expirations (150, 151). As a result of these patent expirations on popular drugs, there has been an explosion of new generic drug applications.
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TABLE 8-16. Recent
and pending patent expirations
Brand Name Procardia Tenormin Ceclor Cardizem Feldene Naprosyn Xanax Tagamet Seldane Micronase Capoten Zantac Trental Noroxin
Generic Name Nifedipine Atenolol Cefaclor Diltiazem Piroxicam Naproxen Alprazolam Cimetidine Terfenadine Glyburide Captopril Ranitidine Pentoxifylline Norfloxacin
Patent Expiration Date* 1991 1991 1992 1992 1992 1993 1993 1994 1994 1994 1995 1995 1997 1998
*Extentions may be granted Perhaps the major factor promoting generic drug utilization is the increased attention to containing health-care costs. Pushed by a drive for lower-cost medication by federal and state governments, private insurers, corporate benefit managers, regulatory agencies and consumer groups, generic drug usage is at a peak. Additional impetus could come from health care reform, wherein generic drugs are viewed as a key to controlling pharmaceutical costs. Managed care programs are expected to cover more than 70% of all outpatient prescriptions by the end of the decade, with an accompanying greater demand for generic products (152). Thus the demand for generic drugs will continue to rise, in a climate that favors health care reform, lower- cost medications and broad-based prescription benefits (153). With the increasing availability of generic drugs, pharmacists are called upon more and more often to select a patients drug product from a myriad of multisource products. The pharmacists role in product selection has increased dramatically in the past decade and the proper selection of multisource drug products has become a major professional responsibility of pharmacists. Although most pharmacists do not, realistically, evaluate the bioequivalence of two products from blood level data, professional judgement does need to be exercised; and this requires an understanding and application of the biopharmaceutical principles discussed.
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8.2.6
THE ORANGE BOOK

One of the factors that led to the widespread repeal of the state anti-substitution laws in the 1970s was an effort by the states to contain drug costs and the establishment of maximum allowable costs (MACs) for reimbursement of drugs under Medicaid. By allowing the pharmacist to select the manufacturer of a drug, the less- expensive generic version could be dispensed. However, before the pharmacist could knowledgeably select a generic drug, he had to know which generics were bioequivalent to the innovator product and thus, interchangeable. (There was substantial evidence at this time that not all pharmaceutically equivalent products were bioequivalent). To answer this need, the states began preparing either positive or negative formularies, often turning to the FDA for assistance in this undertaking. In response to the many requests for assistance from the states in developing their formularies, the FDA Commissioner notified state officials of FDAs intent to provide a list of all prescription drug products that have been approved as being safe and effective, along with therapeutic equivalence determinations for multisource prescription products. This list, entitled Approved Drug Products with Therapeutic Equivalence Evaluations, more commonly known as "The Orange Book" was first published in 1980 and is now in its 14th edition. It is published annually and updated monthly. The Orange book is generally considered to be the most reliable guide for determining which drug products are therapeutically equivalent. The Prescription Drug Products List contains:
1. 2.
all the drug products approved by the FDA as being safe and effective under the Federal Food, Drug and Cosmetic Act, and 2.the therapeutic equivalence evaluations for all approved multisource prescription drug products (those pharmaceutical equivalents available from more than one manufacturer).
Currently, multisource products comprise almost 80% of the approximately 10,000 drugs on the Prescription Drug Product List. The therapeutic evaluation for these products have been prepared to serve as information and advice to state health agencies, pharmacists and prescribers to promote knowledgeable drug product selection and to foster containment of health costs.
8.2.7
THERAPEUTIC EQUIVALENCE
Drug products are considered to be therapeutic equivalents if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect when administered to patients as specified in the labeling (90). In general, the FDA
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evaluates as therapeutically equivalent those drug products that satisfy the following general criteria:
1. 2.
They are approved as safe and effective. They are pharmaceutical equivalents; i.e. they
a.
contain identical amounts of the same active ingredient in the same dosage form and route of administration, and meet compendial and other applicable standards for quality, purity, strength and identity.
b. 3.
They are bioequivalent. Bioequivalence may be established by either an in-vivo or in-vitro test, depending on the drug. If the drug presents a known or potential bioequivalence problem then an appropriate standard must be met which demonstrates a comparable rate and extent of absorption. They are adequately labeled. They are manufactured in compliance with Current Good Manufacturing Practice regulations.
4. 5.
The FDA believes that drug products meeting the above criteria are therapeutically equivalent and can be substituted with the full expectation that the substituted product will produce the same therapeutic effect as the prescribed product.
8.2.8
THERAPEUTIC EQUIVALENCE EVALUATION CODESThe FDA uses a two-letter coding system for multisource products. The first letter in the code allows users to determine whether a particular product has been evaluated therapeutically equivalent to other pharmaceutically equivalent products. The second letter in the code provides additional information about the basis of FDAs evaluation. The various categories are summarized in Table 8-17 on page 40.
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TABLE 8-17. Therapuetic "A" Drug Products
equivalency codes
"B" Drug Products Drug products the FDA does not consider to be therapeutically equivalent; i.e. drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. Often the problem is with specific dosage forms rather than with the active ingredient. These products are classified as "B" for one of three reasons: 1. The active ingredients or dosage forms have documented or potential bioequivalence problems, and no adequate studies demonstrating bioequivalence have been submitted. The quality standards are inadequate or the FDA has insufficient basis to determine therapeutic equivalence. 3. The drug product is under regulatory review. These products are designated as: BC BD Controlled-release tablets, capsules and injectables Active ingredients and dosage forms with documented bioequivalence problems Delayed-release oral dosage forms (e.g. enteric-coated products) Products in aerosol-nebulizer drug delivery systems Active ingredients and dosage forms with potential bioequivalence problems Suppositories or enemas that deliver drugs for systemic absorption Products having drug standard deficiencies Topical products with bioequivalence issues Insufficient data to determine therapeutic equivalence Drug products requiring further FDA investigation and review to determine equivalence
Drug products the FDA considers to be therapeutically equivalent; i.e. drug products for which: 1. There are no actual or potential bioequivalence problems. These are designated as: AA AN AO AP AT 2. Products in conventional dosage forms Solutions and powders for aerosolization Injectable oil solutions Injectable aqueous solutions Topical products
2.
Actual or potential bioequivalence problems have been resolved via adequate in vivo and/or in vitro tests. These are designated as AB.
BE
BN BP
BR
BS BT BX B*
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There are two basic categories into which multisource drugs have been placed, "A" or "B". Drug products rated "A" are products that the FDA considers to be therapeutically equivalent to the pharmaceutically equivalent original product. These fall into one of two classes:
1. 2.
There are no known or suspected bioequivalence problems. Actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.
Category "B" consists of drug products that the FDA does not at this time consider to be therapeutically equivalent to the pharmaceutically equivalent reference product. Certain types of products are rated B by virtue of their specialized dosage forms. For example, controlled-release dosage forms are rated BC, unless bioequivalence data have been submitted as evidence of equivalence. In this case, the product would be coded AB. The fact that a product is in the "B" category does not mean it should not be dispensed; it simply means that a B rated product should not be substituted for a pharmaceutically equivalent product. For example, glyburide is marketed as Micronase and DiaBeta by two different manufacturers. Both these products are clinically effective, but because bioequivalence between the two has not been studied, they are B rated and are not interchangeable. To avoid possible significant variations among generic drugs as a result of comparison to different reference drugs, the FDA began designating a single reference listed drug against which all generic versions must be shown to be bioequivalent. The reference listed drug is identified by the symbol "+" in the Prescription Drug Product List. This symbol was used for the first time in the 1993 edition of the Orange Book.
Limitations and exclusions-
Although the Orange Book is a very valuable reference for pharmacists performing drug product selection, it has certain limitations, which must be recognized. It was not intended to serve as a single comprehensive reference on all multisource drugs. Many prescription drug products are not listed in the Orange Book, making evaluation of their therapeutic equivalence difficult, if not impossible. Exclusion of a drug from the Orange Book means that the FDA has not evaluated its safety, efficacy and quality. Table 18 lists the classes of products excluded from the Orange Book. Because the equivalence of these excluded products is unknown, interchanging of these products should be avoided.
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TABLE 8-18. Drug
Products excluded from the Orange Book
1.
Drugs marketed before the passage of the Federal Food, Drug, and Cosmetic Act of 1938. These are not included because the FDA has not reviewed these drugs for safety and efficacy and does not have the necessary information to make therapeutic equivalence evaluations. Examples: digoxin, morphine, codeine, thyroid, levothyroxine, phenobarbital and nitroglycerin Drugs for which the FDA has no NDA or ANDA on file. Examples: Anusol-HC, Naldecon (and their generic counterparts) Drugs still undergoing Drug Efficacy Study Implementation (DESI) review. These are drugs that were marketed between 1938 and 1962 on the basis of safety, but not efficacy. Although most of these drugs have been reviewed and are listed in the Orange Book, there are still a number of these pre-1962 drugs which have not yet been classified as "effective" under the DESI program, and are not listed. Examples: nitroglycerin controlled-release capsules, pentaerythritol tetranitrate, isocarboxazid, hydrocortisone-iodochlorhydroxyquin cream In addition, nitroglycerin transdermal patches are still undergoing efficacy studies, and are not listed in the Orange Book.
2.
3.
Another limitation of the Orange Book that all pharmacists should be aware of is that the drug listings contain the names of only the companies that actually hold an approved NDA or ANDA; they may not be the same as the actual manufacturer or distributor. It is fairly common practice for a drug to be manufactured pursuant to an NDA or an ANDA but distributed under license agreement by another company. In this instance, the distributor would not be listed in the Orange Book. Since pharmacists are, understandably, generally unaware of the name of the actual holder of the NDA or ANDA, it is often difficult for them to determine the therapeutic equivalence of a particular multisource product if it is not listed in the Orange Book. For example, there are over thirty manufacturers and distributors marketing approved, therapeutically equivalent versions of furosemide 40 mg tablets (154). However, only twelve of these companies are actually listed in the Orange book, since these are the actual holders of an NDA or ANDA. Therefore, the pharmacist would have to verify the therapeutic equivalence evaluation of the non-listed products by obtaining the information from the manufacturer, packager, or supplier.
Legal status and pharmacists responsibility-
The Orange Book per se has no legal status. The FDA stresses that it is a source of information and advice on drug product selection, but it does not mandate the drug products which may be dispensed nor the products that should be avoided. Thus, the Orange Book does not carry the weight of regulation or law, and the FDA assumes no liability for drug products selected on the basis of its equivalence evaluation. The Orange Book points out that "FDA evaluation of therapeutic equivalence in no way relieves practitioners of their professional responsibilities in prescribing and dispensing such products with due care." There are circumstances where pharma-
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cists will have to exercise professional care and sound judgement in selecting a drug product for a particular patient. Although two products may be rated as being therapeutically equivalent in the Orange Book, they may not be equally suitable for a particular patient. Drugs that share the "A" code may still vary in ways that could affect patient acceptance. They may differ in shape, color, taste, scoring, configuration, packaging, preservatives, expiration time, and in some instances, labeling. If products with such differences are substituted for each other, there is potential for patient confusion or decreased patient acceptance. For example, a patient may be sensitive to an inert ingredient in one product that another product does not contain. Or, a patient may become confused if the color or shape of a product varies from that to which he has become accustomed. A patient may reject the administration of a substituted product because of differences in taste or appearance. When such characteristics of a specific product are important in the treatment of a particular patient, the pharmacist should select a product with these considerations in mind as well as bioequivalence. Despite its limitations and shortcomings, the Orange Book is a very useful guide for rational product selection. Pharmacists can utilize the information presented there, in combination with sound professional judgment, to make decisions on behalf of their patients regarding the choice of the most appropriate drug product.
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8.3 Drug Product Selection

Multisource drug product selection has become a very important component of contemporary pharmacy practice. The National Prescription Audit (NPA) has, for some years now, been chronicling the heightened role played by pharmacists in the selection of which brand (or generic version) of a multiple-source drug will be dispensed to the patient. From 1983 through 1993, the pharmacists role in selecting brand or generic products for dispensing has increased dramatically, as shown in Table 19. In the first half of 1993, pharmacists controlled 41% of dispensing decisions, as compared to 16% in 1983. It is evident that the substitution trend is strong and is continuing to gain ground. This expansion of pharmacys province in brand choice decisions is the result of several factors: economic pressures for lower prescription costs, repeal of anti- substitution laws and increased acceptance of generics by patients, physicians and pharmacists. Perhaps the most significant factor in escalating the overall level of pharmacists brand choice decisions has been the expiration of the patents of high- volume pioneer brands, as previously discussed. This has resulted in significant expansion in the potential for pharmacist choice.
TABLE 8-19. Pharmacists
Brand Selection
Year
Percent of all new prescriptions involving pharmacists brand choicea
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 Jan.-June 1993
16 18 20 23 25 27 30 32 34 38 41
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8.3.1
CONSIDERATIONS IN SELECTING A MANUFACTURER

The selection of a pharmaceutical manufacturer of a multisource product has become an important professional responsibility for pharmacists. This responsibility has become an especially critical part of a pharmacists role in light of the increasing number of generic products available and in light of some of the problems that have occurred in the generic drug industry (the "generic drug scandal" of 1989). The pharmacist is entrusted by the public to select manufacturers that offer the best quality at the best price.
So how does the pharmacist select the manufacturer of a multisource drug product? What factors should be considered?
Thoughtful selection of a multisource drug product is not an easy task, and requires a consideration of not only the drug product itself, but also the manufacturer, and in some cases, the patient. Several options are open to the pharmacist performing drug product selection: to select a product solely on the basis of economics, to select a product on the basis of the reputation of the manufacturer, or to make a decision based on product bioequivalence and quality and on the basis of the products conformity with official compendial standards and with those established by the FDA. The first option, while offering a financial advantage, does not provide assurance of therapeutic efficacy. The second option, although subjective, is easily applied and does offer a degree of security to the pharmacist. The third option is the most challenging to the pharmacists, requiring the application of principles of biopharmaceutics and pharmacokinetics in arriving at a decision. Ideally, the pharmacist should take into consideration all the above options when selecting a drug product for a patient. When pharmacists were asked which factors are most important to them in selecting a manufacturer of a generic product, the primary criteria indicated were the reputation and quality of the company (159-162). Bioequivalence to the brand-name product was also ranked as being an important factor in product selection. However, the most frequently used sources for assessing bioequivalence were manufacturer reputations (based previous experience) and product literature provided by the distributing company. Company-sponsored material must be carefully evaluated. Unfortunately, promotional literature does not generally contain sufficient data to permit rational analysis of whether or not products are bioequivalent (163). Also, relying on personal methods of information gathering for assessing bioequivalence is not very reliable. Interestingly, only 23% of pharmacists reported using the Orange Book in assessing bioequivalence (161). Selection of drug products should be based on sound scientific and clinical grounds. Developments in the science of pharmacokinetics and the related area of bioavailability have given pharmacists the tools necessary to make sound choices among multisource products. In response to the professions need for information and advice on how to select appropriate drug products from multiple sources, the American Pharmaceutical Association formed a Bioequivalency Working Group to establish guidelines for product selection (Table 8-20 on page 47) (164). This Group made
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recommendations of factors that pharmacists should consider when selecting drug products to be dispensed to their patients. If pharmacists consider the factors indicated as part of the professional judgement process when making drug product selections, it is likely that the best interest of the patients will be served. The appropriate selection of a generic drug product involves much more than just cost considerations or reliance on state and federal laws and regulations. It requires a knowledge of the drug entity and its physical and chemical properties, the condition to be treated, and its significance, and the history and attitude of the manufacturer. One of the criteria often used to evaluate a manufacturers record is the number and type of recalls of that companys products. Product selection may also require taking into consideration the patient, the disease, previous drug therapy, and duration of therapy before a decision is made. Gagnon presented a step-by-step analysis procedure that pharmacists can use in evaluating multisource suppliers of a pharmaceutical product (Table 8-21 on page 49) (165). Using this procedure, each manufacturer is rated in each area listed, thus enabling the pharmacist to make the most rational choice.
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TABLE 8-20. Guidelines
for product selection
DISPENSING DECISIONS ? State Rules and Regulations. Pharmacists should be cognizant of legal requirements that address the issue of drug product selection. Many states have positive or negative formularies to provide guidance in drug product selection. ? Bioequivalency Information/Orange Book Ratings. Only products with proven bioequivalency should be selected to be dispensed in lieu of the innovator product. Products that are listed in the FDAs Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) as "A" rated should be selected when such products are available. For pre-1938 drugs, the selection should be based on data obtained from the literature, because bioequivalency testing is not required by the FDA for these drug products. ? Dosage Form. The type of dosage form should be considered whenever one drug product is selected from among multisource drug products. This is especially true with extended or delayed release medications. ? Previous Drug Use. Two questions should be considered regarding previous drug product usage. First, is the prescribed drug a continuation of already successful therapy? If it is, the impact of any change in source of the medication should be considered. The pharmacist should also know which product the patient was using previously, including any medications in the hospital if the patient was recently discharged. Second, was the original product dispensed a generic product? If so, preference should be given to continuing to dispense the same generic product from the same source. ? Patient Status. The pharmacist should consider how well controlled the patient is and how susceptible that patient might be to small changes in drug absorption. If a patient has labile control or has experienced great difficulty in achieving control, the pharmacist should continue therapy with a product from a single source throughout therapy. ? Diseases. The seriousness of the disease and its potential impact on the patient may influence the pharmacists willingness to change products. ? Drug Class or Category. Drugs with narrow therapeutic ranges and with known clinically significant bioavailability problems should be substituted with care and/or after discussion with the prescriber. ? Cost. The cost of the product , while an important consideration, should be a secondary consideration in selecting among products judged by the pharmacist to be bioequivalent. ? Patient Opinion. An informed patient, cooperating with a physician and pharmacist in his or her drug therapy, is an important element in ensuring the best possible therapeutic outcomes. The pharmacist should take into account the patients need when selecting from multisource drug products and inform the patient of any potential consequences associated with alternate product selections.
PURCHASE DECISIONS ? Current State Laws and Regulations. Some states have positive or negative formulary systems that place regulatory restrictions on the products considered therapeutically equivalent. The state formulary may not always be in agreement with classifications listed in the FDAs Orange Book. Therefore, pharmacists should be familiar with both. ? Bioequivalency Information/Orange Book. Products shown to be bioequivalent through reference to the Orange Book or other reliable source of bioequivalency information are preferred. Purchase decisions for drugs marketed prior to 1938 should be based on data obtained from the literature or the manufacturer, because bioequivalency testing may not be required by the FDA for these drug products. ? Drug Category. Greater attention should be given to purchasing strategies for drug products used for serious or life-threatening diseases and in situations where therapeutic activity of the product is confined to a narrow range of biologic fluid concentration. ? Availability. A continuous supply from the same manufacturer is essential even in the event that the distributor has changed to ensure that refills of prescriptions will contain the same product as originally dispensed. However, in those instances when the manufacturer of a generic drug product has to be changed, care should be exercised to ensure that the new drug product is equivalent to the formerly stocked drug product. ? Suppliers Reputation. The reputation of the manufacturer in terms of its ability to adhere to good manufacturing practices (GMP) that ensure that each dosage form is manufactured correctly and in a consistent manner is an important consideration. When purchasing a product from a distributor rather than directly from the manufacturer, the procedure used by that supplier in selecting manufacturers for multisource products is also an important consideration. Establishment Inspection Reports and recall reports are available from FDA through a Freedom of Information (FOI) request. These are valuable tools in this decision. ? Cost.
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TABLE 8-21. Evaluation
of Multi-source Suppliers
Factors and Cues

Product Information Size(s) available Dosage form(s) available Bioequivalence data results using Orange Book Existence of identification codes on solid dosage forms Average number of months between product receipt and expiration date Results of cost-effectiveness information from manufacturer Complete product literature provided from manufacturer Strength(s) available State/federal formulary rules, e.g., MAC limits Economics Price(s) Deals and other discounts Terms of sale Clear and equitable pricing policy Large sizes available at discount prices Product Quality NDA/ANDA on file at FDA Pharmaceutical elegance of products, e.g., broken tablets, powder in bottles Less than 3 year FDA on-site inspection Results of on-site FDA inspection Company willing to allow pharmacist to inspect plant Results of quality control analysis Company willing to supply samples for testing Product acceptance by physicians Product acceptance by patients Service Quality Returns policy Rapid resolution of complaints Company product availability record Liability protection policy Terms of unconditional guarantee Company commitment to education of practitioners Availability of company representative Existence of 24-hour emergency customer service telephone number Product availability through wholesalers Ease of placing orders Company customer information center, including an 800 number Company Reputation Number of recalls in last 3 years Severity of recalls in last 3 years Who initiated recalls (FDA or company) Company has a recall strategy Other regulatory actions against company Company has wide product line FDA quality assurance profile Company has crisis communication strategy
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Pharmacists have the responsibility of correctly selecting and dispensing multisource products that will have the greatest likelihood of achieving a positive therapeutic outcome in a cost-effective manner. The more information pharmacists have about a product and its manufacturer, the more likely they will be to make the most appropriate choice. Price cannot be the single factor in selecting a product. It is also clear, as Joseph Oddis stated, "Rational drug product selection entails far more than simply consulting the FDAs Orange Book or looking at the price catalogue" (166).
8.3.2
SPECIAL CASES
While in most situations selection of drug products that are therapeutically equivalent can be done without undue complications, there are some circumstances where problems could occur. Depending on the drug, its formulation, the disease being treated, and the condition of the patient, generic substitution may not be advisable. Some of these special situations require extra attention and handling by the pharmacist. There are a number of drugs that could present problems when interchanged. Drugs that are poorly water soluble may have inherent problems with rate and extent of dissolution, resulting in poor or variable bioavailability. Drugs that are potent and thus present in very low amounts in a dosage form could present problems due to formulation factors. Some dosage forms may have inherent bioavailability problems, such as controlled-release products. And drugs which are considered "critical" also need special consideration. "Critical" drugs have been defined as drugs with a narrow therapeutic range, where a change in plasma concentration might result in adverse clinical outcome; drugs that are considered primarily for control of a disease rather than for alleviation of temporary symptoms; and drugs that have inherent or historical bioavailability or bioequivalence problems (8, 19). Seven classes of drugs have been identified that have demonstrated bioequivalence problems or, because of the nature of the product, have the potential for creating therapeutic problems if product interchange is permitted (Table 822 on page 51) (167-168).
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TABLE 8-22. Catagories
of drugs with demonstrated bioequivalence problems Digitalis glycosides - digoxin Warfarin anticoagulants Theophylline products Thyroid preparations (including levothyroxine) Conjugated and esterified estrogens Antiarrhythmic agents - quinidine salts - procainamide Anticonvulsants - phenytoin - carbamazepine - primidone
There have been numerous reports of drugs implicated in therapeutic problems due to bioinequivalence difficulties. In addition to those in the categories given in Table 8-22 on page 51, these include furosemide, propranolol, diazepam, prednisone, nitrofurantoin, and amitriptyline (20, 126, 167, 169-180). Although the documentation implicating these drugs in therapeutic failures due to bioavailability problems is primarily anecdotal in nature (and thus disregarded by the FDA), the performance of these products should still be closely observed and monitored, and care should be taken when selecting drugs from these categories. In addition to "critical" drugs, critical patients and critical diseases have also been identified when special care should be taken in performing product selection (8, 166). Critical patients are the very old and the very young, those suffering from multiple diseases who are managed with multiple drugs, and those who live alone, making observation of adverse drug effects unlikely. Critical diseases are generally chronic in nature and difficult to stabilize, where drug-disease interactions can present major problems (e.g. congestive heart failure, asthma, diabetes, cardiac disorders, and psychoses). In all the above special "critical" circumstances, there is a high risk of therapeutic problems, and product selection requires extra attention and precautions. In fact, product substitution and interchange in these cases is generally discouraged. Once a product (brand or generic) has been selected for a course of therapy, the pharmacist should not change to a different product if it can be avoided. If interchange is performed, it should be done only with the utmost care, and the patient should be monitored for any adverse outcomes.
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Pharmacists professional responsibility-
Drug product selection has been and continues to be a primary and challenging professional responsibility of pharmacists. It is one where the pharmacist must exercise professional care and sound judgement to make decisions on behalf of the patient to maximize safety and efficacy, while minimizing cost. Pharmacists have a professional obligation to patients to take whatever steps are necessary to assure themselves that the medicines they are dispensing are safe and effective. Although some of this activity is currently constrained by bureaucratic and regulatory restrictions that often discourage, or entirely prevent, individual professional evaluation and initiative, with a greater appreciation and understanding of the scientific, clinical, and regulatory issues that form the basis of the process, pharmacists can make decisions that result in better patient care. Pharmacists must take steps to ensure the quality and integrity of the drug products dispensed to their patients. To accomplish this, pharmacists must look to pharmaceutical manufacturers to supply them with a quality product they can trust. Thus, the manufacturer of a multisource product must be carefully selected to ensure that the products they supply are of proper quality. If necessary, pharmacists should conduct independent research into the reputation and integrity of the manufacturer, or, if products are purchased through a buying group, should make sure that established policies and guidelines are in place to review multisource products. When considering purchasing drug products, the pharmacist should request the manufacturer to provide certain documentation and information, and should then evaluate this information (see Table 23).
TABLE 8-23.
Considerations when evaluating a Multi-Source vendor
1.Willingness to supply requested information 2.Bioavailability and bioequivalence data 3.Dissolution testing results 4.FDA bioequivalence rating 5.The actual manufacturer of the product, if not the supplier 6.FDA inspection reports 7.History of the manufacturers recall record 8.Willingness of the manufacturer to permit on-site visitations 9.Evaluate economic considerations such as price, shipping, terms, discounts, insurance, return policies, and packagng.
And finally, pharmacists can counsel the patients on the importance of using the same drug product throughout a course of therapy, even though they might go to a different pharmacy. To further emphasize this, it has been suggested that the initial prescription and subsequent refills of a drug product considered questionable for interchange should contain auxiliary labeling that stresses the importance of continuing to use that product (167). Drug product selection is an important professional responsibility, but it is not an easy task. It requires the pharmacist to use his/her current knowledge, and
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all the currently available information in order to arrive at and render a decision regarding the most appropriate product to use for a specific patient.
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8.4 Summary
With the dramatic increase in the availability and utilization of generic drug products in recent years, pharmacists are being faced with an ever-increasing array of multisource products. Appropriate selection of a product from the plethora of products on the market is not always an easy task; the quality of the drug product must be considered, as well as the cost. The principles of biopharmaceutics indicate that the formulation and method of manufacture of a drug product can have a marked effect on the bioavailability of the active ingredient. Thus, generic equivalents may not necessarily be therapeutically equivalent. Guidelines and criteria have been established by the FDA to help judge whether one product can be substituted for another with assurance of equivalent therapeutic effect. For pharmacists to provide informed product selection, it is essential that they be knowledgeable about, and familiar with, these guidelines and criteria. This requires an understanding of bioavailability, bioequivalence, and how they are determined. The pharmacist can serve a major role in ensuring that only high quality products are dispensed, and in this way help reduce health care costs without compromising quality of care.
Acknowledgment
The author gratefully acknowledges the assistance of Umesh V. Banakar in the preparation of this manuscript.
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8.4.1
QUESTIONS
1.
The term bioavailability refers to the

a. b. c. d. e.
dissolution of a drug in the gastrointestinal tract. amount of drug destroyed in the liver by first-pass metabolism. distribution of drug to the body tissues over time.
relationship between the physical and chemical properties of a drug and its systemic absorption. measurement of the rate and amount of drug that reaches the systemic circulation.
2.
The bioavailability of various drug products can be evaluated by comparing their plasma concentration-time curves. The three most important parameters of comparison that can be obtained directly from the curves are
a. b. c. d.
biologic half-life (t1/2), absorption rate constant, area under the curve (AUC). time of peak concentration (tmax), absorption rate constant, elimination rate constant. maximum drug concentration (Cmax), time of peak concentration (tmax), duration of action. area under the curve (AUC), time of peak concentration (tmax), maximum drug concentration rate of elimination, area under the curve (AUC), rate of absorption.
(Cmax).
e.
3.
Two products are bioequivalent if they

a. b. c. d. e.
contain the same amount of the same active ingredient. have equal areas under the curve after the administration of the same dose. have the same value for Cmax after administration of the same dose.
have equivalent rates and extents of absorption of the drug after administration of equal doses. are pharmaceutically equivalent.
4.
If an oral capsule formulation of drug A produces a plasma concentration- time curve having the same area under the curve (AUC) as that produced by an equivalent dose of drug A given intravenously, it can generally be concluded that:
a. b. c. d. e.
there is no advantage to the IV route. the absolute bioavailability of the capsule formulation is equal to 1. the capsule formulation is essentially completely absorbed. the drug is very rapidly absorbed. b and c are correct.
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5.
5.Which of the following is NOT a criterion for therapeutic equivalence of two products, according to the FDA?
a. b. c. d. e.
They must be pharmaceutical equivalents. All ingredients - active and inactive - must be the same. They have been manufactured in compliance with Good Manufacturing Practices. They are bioequivalent. They are approved as safe and effective by the FDA.
6.
6.A test oral formulation has the same area under the plasma concentration- time curve as the reference formulation. This means that the two formulations
a. b. c. d. e.
are bioequivalent by definition. deliver the same total amount of drug to the body but are not necessarily bioequivalent. are bioequivalent if they both meet USP dissolution standards. deliver the same total amount of drug to the body and are, therefore, bioequivalent. have the same rate of absorption.
7.
7.In-vitro dissolution rate studies on drug products are useful in bioavailability evaluations only if they can be correlated with
a. b. c. d. e.
in-vivo bioavailability studies in humans. the chemical stability of the drug. USP disintegration requirements. in-vivo studies in at least three species of animals. the therapeutic response observed in patients.
8.
8.Which of the following statements regarding bioequivalence is TRUE?

a.
If the mean AUC and Cmax values for a generic product are within + 20% of those of the reference product, the two products are bioequivalent. If we can be 90% certain that the mean values of AUC and Cmax for two products are within 80% to 125% of each other, then the two products are considered bioequivalent.
b.
c.
Bioequivalence studies are generally conducted in a panel of patients consisting of the target population for which the drug is intended. Bioequivalence studies are generally conducted as multiple-dose studies utilizing the cross-over design. If two products are shown to be bioequivalent, we can always say with certainty that they will be therapeutically equivalent.
d. e.
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9.
9.Which of the following statements about the FDA Orange Book is TRUE?
a.
Drugs that are excluded from the Orange Book are not safe and effective and should not be dispensed. It contains therapeutic equivalence evaluations for all the drugs approved by the FDA. Products placed in the "B" category should not be dispensed.
b. c. d. e.
The Orange Book is an official compendium, and pharmacists can legally only dispense those products listed as bioequivalent. The drug listings contain the names of only the companies that actually hold an approved NDA or ANDA for a drug.
10.
10.Growth in the utilization of generic drug products can be attributed to

a. b. c. d. e.
passage of the 1984 Waxman-Hatch Act. expiration of patents of many popular brand products. pressures to reduce health care costs. the growth of managed health care organizations. all of the above.
8.4.2
ANSWERS TO QUESTIONS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. e d d e b b a b e e
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8.5 Bioavailibility Equations

The following set of equations were used to solve the bioavailability problem set. The problem sets for the first two drugs have been done for you. The others are done exactly the same way. The answers follow the problems. 1. AUMC iv MRT iv = --------------------- as discussed in chapter 4. AUC iv 1 k = --------------MRTiv ln 2 t 1 2 = ------k Cp 0 iv = AUC k Dose iv V d = ---------------Cp 0 iv Cp iv = Cp 0 e
kt
2.
3. 4.
5.
6.
7.
AUC oral Dose iv f = --------------------- ---------------Dose oral AUC iv AUMC po - as discussed in chapter 4 MRT po = ---------------------AUC po MAT po = MRT po MRT iv 1 k a = ----------MAT ka ---- ln k t p = --------------ka k
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10.
11.
8-58
12.
kt k t fD k a - ----------- (e p e a p) Cpmax = ----V ka k
14. 15.
( AUC generic ) ( Dose generic ) Relative Bioavailability (R.B. or C.B.) = --------------------------------------------------------------------( AUC Brand ) ( Dose Brand ) Bioequivalent: Yes if all three: 0.80 < CB < 1.25 t p g eneric - < 1.25 0.80 < ------------t p bran d C p ma x g eneric - < 1.25 0.80 < ----------------------C p max brand
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8.6 Problems
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Caffeine
(Problem 8 - 1)
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral administration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intravenously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this experiment is given below. Fill in the empty cells.
TABLE 8-24. Caffeine
Parameter Dose (mg/kg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 2.5 63.1
Oral Solution 2.5 60.7
Brand Tablet 2.5 60
Generic Tablet 2.5 57
Bioequivalence
1442
1556.8
1600
1723
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Cefetamet Pivoxil
(Problem 8 - 2)
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the approprate cells. .
Parameter Dose (mg) ug ------AUC mL hr ug 2 ------AUMC mL hr MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) IV 250 30.64 Oral Solution 500 53.68 Brand Tablet 500 50 Generic Tablet 500 47 Bioequivalence
101.66
191.64
205.6
225.3
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Cefixime
(Problem 8 - 3)
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a washout period between the administration of each dosage form. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 200 47
Brand Capsule 200 23.6
Generic Capsule 200 20.2
Bioequivalence
183.3
162.8
187.5
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Ceftibuten
"The pharmacokinetics of ceftibuten in humans"
(Problem 8 - 4)
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram positive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus dose of ceftibuten. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 200 75.2
Oral Solution 400 65.9
Brand Tablet 400 64.2
Generic Tablet 400 64
Bioequivalence
211.2
213.4
220
208
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Cimetidine
(Problem 8 - 5)
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Journal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer disease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained from this experiment is given below.
IV 300 3.81
Generic Tablet 300 2.50
Bioequivalence
5.33
11.73
10.73
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Diurnal Variability in Theophylline Bioavailability
(Problem 8 - 6)
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Pharmacokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data obtained from this experiment for the time period between midnight and noon is given below. From the preceding data, please calculate the following:
IV 500 160.25
Brand Tablet 500 140
Bioequivalence
1821
1662
1785
1700
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cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine (FTC) (Problem 8 - 7)

Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2,3-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 100 265
Bioequivalence
19514
12600
13125
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Hydromorphone
(Problem 8 - 8)
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydromorphone on separate days. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
Parameter Dose (mg) ug - hr AUC ----L ug - hr 2 AUMC ----L MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ---- L Vd (L) ug Cp at 1 hour ---- L f ug ----Cpmax L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 2 83
Brand Tablet 4 87.2
Generic Tablet 4 96
Bioequivalence
289.4
401
432
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Isosorbide Dinitrate
(Problem 8 - 9)
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Therapeutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure. In this study volunteers received a 5 mg intravenous dose given over 5 minutes and a 10 mg tablet. The different dosage forms were separated by a washout period. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ug - hr AUC ----L ug - hr 2 AUMC ----L MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ---- L Vd (L) ug Cp at 1 hour ---- L f ug Cpmax ---- L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 5 370.3
Brand Tablet 10 158
Bioequivalence
487
310
305
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Ketanserin
(Problem 8 - 10)
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28, (1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ng - hr AUC ------ mL ng - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------ mL Vd (L) ng Cp at 1 hour ------ mL f ng Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 10 247
Brand Tablet 40 520
Bioequivalence
3991
8922
8922
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Methotrexate
(Problem 8 - 11)
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis", British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The importance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis. Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as a 15 mg dose. The following data was obtained: From the preceding data, please calculate the following:
Parameter Dose (mg) nmole - hr AUC -------------- L nmole - hr 2 AUMC -------------- L MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) nmole Cp0 -------------- L Vd (L) nmole Cp at 1 hour -------------- L f nmole Cpmax -------------- L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 15 2752
Bioequivalence
15887
18400
18500
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Moclobemide
(Problem 8 - 12)
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Journal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 150 2.58
Bioequivalence
6.35
5.91
5.90
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Nalbuphine
(Problem 8 - 13)
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study, volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 10 86.9
Bioequivalence
288
306
280
270
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Nefazodone
(Problem 8 - 14)
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ng - hr AUC ------ mL ng - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------ mL Vd (L) ng Cp at 1 hour ------ mL f ng Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 10 6023
Oral Solution 10 829
Brand Tablet 10 800
Bioequivalence
29283
4875
4800
4500
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Ondansetron
(Problem 8 - 15)
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Pharmaceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailability of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
IV 8 246.5
Brand Tablet 8 139
Bioequivalence
1138
795
870
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Omeprazole
(Problem 8 - 16)
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Pharmacology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) mole - hr AUC -------------- L mole - hr 2 AUMC -------------- L MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) mole Cp0 -------------- L Vd (L) mole Cp at 1 hour -------------- L f mole --------------Cpmax L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 20 3.2
Bioequivalence
3.2
5.25
4.5
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Paroxetine
(Problem 8 - 17)
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg and slow intravenous infusion of 23 - 28 mg. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) ng ------AUC mL hr ng 2 ------AUMC mL hr MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------ mL Vd (L) ng Cp at 1 hour ------ mL f ng ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 28 467
Brand Tablet 45 750
Bioequivalence
6671
11250
10463
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Ranitidine
(Problem 8 - 18)
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986), p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 50 5159
Bioequivalence
53415
78752
84413
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Sulpiride
(Problem 8 - 19)
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups. The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 100 8.27
Bioequivalence
79.1
87.3
91.1
84.5
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8.7 Solutions
8.7.1 CAFFEINE ON PAGE 61
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral administration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intravenously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this experiment is given below. Fill in the empty cells.
TABLE 8-25. Caffeine
Parameter Dose (mg/kg) ug ------AUC mL hr ug 2 ------AUMC mL hr MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L/kg) ug Cp at 1 hour ------ mL f ug ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 2.5 63.1
Oral Solution 2.5 60.7
Brand Tablet 2.5 60
Generic Tablet 2.5 57
Bioequivalence
1442
1556.8
1600
1723
22.9 0.0438
25.7 2.79
26.7 3.81
30.2 7.36
0.358 2.76
0.262
0.136
0.91 2.64 0.78 0.59 0.31
0.96 2.76 1.98
0.95 1.83
.90 1.45 0.79
6.69
8.19
12.1
1.5 0.95 NO
REV. 97.4.22
8-80
1.
AUMC -= MRT = ----------------AUC
ug h 1442 --------------mL ---------------------------= 22.9 2 ug h 63.1 --------------mL
hours
2.
1 1 - = ------------- = 0.044 h 1 k = ----------MRT 22.9 h ln 2 0.693 - = -------------------- = 15.75 h t 1 2 = ------1 k 0.044 h ug h ug 1 Cp 0 = AUC k = 63.1 ------------- 0.0044 h = 2.76 ------mL mL
The horses have an average weight of 500 kg.
3.
4. 5.
mg - 500 kg = 1250 mg Dose = 2.5 -----kg ug mg - = 2.78 -----Cp 0 = 2.78 ------mL L L 2.5 mg kg Dose 1250 mg - = 0.91 ----- = ------------------- = 449.6 L = -----------------------V d = -----------mg kg Cp 0 mg 2.78 -----2.78 -----L L
6.
Cp = Cp0 e
kt
ug 0.044 ( 1 ) ug ------- (e ------= 2.78 ) = 2.64 mL mL
7.
ug h mg 60 ------------2.5 -----AUC oral Dose iv mL kg ----------------------------------------------------------------------------f = = = 0.95 Dose oral AUC iv mg ug h - 63.1 ------------2.5 -----kg mL ug h 1556.8 --------------AUMC mL - = -------------------------------- = 25.7 h = ----------------AUC ug h 60.7 ------------mL
2
8.
MRT po
Where AUMC is that which is given for the oral dose. Where AUC is that which is given for the oral dose. 9.
MAT po = MRT po MRT iv = 25.7 h 22.9 h = 2.79 h
REV. 97.4.22
8-81
10.
1 1 - = --------- = 0.358 hr 1 k a = ----------MAT 2.79 0.358 hr 1 ka ln ----------------------1 ---- ln 0.044 h k - = -----------------------------------------------------= 6.7 hr tp = --------------1 1 ka k 0.358 hr 0.044 hr
0.358 hr ka 0.96 1250 mg fD - ( e kt p e katp ) = ---------------------------------- ------------------------------------------------ ------------- ( e ( 0.044 6.7 ) e ( 0.358 6.7 ) ) Cp max = ----1 449 L V ka k ( 0.358 0.044 ) hr
1
11.
12.
13.
Relative Bioavailability (R.B. or C.B.) = --------------------------------------------------------------------ug mg 57 ------- hr 2.5 ----- mL km - = 0.95 CB = -----------------------------------------------------------ug mg 60 ------- - hr 2.5 ----- mL km
( AUC generic ) ( Dose generic ) ( AUC Brand ) ( Dose Brand )
14.
Bioequivalent: Yes if all three = Yes:
0.80 < CB < 1.25 CB = 0.95 = Yes t p gen eric t p gen eric 12.1 hr - < 1.25 ------------- = --------------- = 1.5 = NO 0.80 < ------------t p b ra nd t p b ra nd 8.19 hr ug 1.45 ------C p max generic mL ----------------------- = ------------------ = 0.79 = NO ug C pma x b rand 1.83 ------mL
C p max gen eric - < 1.25 0.80 < ----------------------C p ma x b rand
REV. 97.4.22
8-82
8.7.2
CEFETAMET PIVOXIL ON PAGE 62
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the approprate cells. .
Parameter Dose (mg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) 0.301 3.97 9.23 1.26 0.678 IV 250 30.64 Oral Solution 500 53.68 Brand Tablet 500 50 Generic Tablet 500 47 Bioequivalence
101.66
191.64
205.6
225.3
3.32
3.57 0.252
4.11 0.794
4,79 1.48
ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 9.23
27.1 6.83 12.62 9.03 5.91
0.88 13.1
0.82 9.6
0.77 7.4 0.77
0.70
1.49
2.15
1.44 0.94 NO
1.
mg h 101.66 ---------------AUMC L - = ---------------------------------MRT = ----------------= 3.32 hours 2 AUC mg h 30.64 ---------------L

Where AUMC is that which is given for the intravenous dose. Where AUC is that which is given for the intravenous dose.
REV. 97.4.22
8-83
2.
1 1 - = ------------- = 0.301 h 1 k = ----------MRT 3.32 h ln 2 0.693 - = --------------------t 1 2 = ------= 2.3 h 1 k 0.301 h mg h mg - 0.301 h 1 = 9.22 -----Cp 0 = AUC k = 30.64 -------------L L Dose 250 mg - = ------------------ = 27.06 L V d = -----------Cp0 mg 9.24 -----L Cp = Cp 0 e
kt
3.
4.
5.
6.
mg 0.301 ( 1 ) mg -----= ) = 6.84 ----- 9.24 L ( e L
7.
mg h 53.68 -------------AUC oral Dose iv L 250 mg - = ---------------------------- ---------------------------- = 0.876 f = --------------------- ---------------mg h Dose oral AUC iv 500 mg 30.64 -------------L mg h 191.64 ---------------AUMC L - = ---------------------------------- = 3.57 h = ----------------AUC mg h 53.68 -------------L
2
8.
MRT po
Where AUMC is that which is given for the oral dose. Where AUC is that which is given for the oral dose. 9. 10.
MAT po = MRT po MRT iv = 3.57 h 3.32 h = 0.252 hr 1 1 - = ------------ = 3.97 hr 1 k a = ----------MAT 0.252 4.0 h 1 ka ln ------------------- 1 ---- ln 0.301 h k - = ------------------------------------------ = 0.7 h t p = --------------1 1 ka k 4.0 h 0.301 h
k t 3.97 hr ka 0.88 ( 500 mg ) mg fD - ( e kt e a ) = -------------------------------- --------------------------------------------- ------------- ( e 0.301 ( 0.7 ) e 3.97 ( 0.7 ) ) = 13.1 -----Cp m ax = ----1 27.1 L L V ka k ( 3.97 0.301 ) hr 1
11.
12.
13.
Relative Bioavailability (R.B. or C.B.) = ---------------------------------------------------------------------
( AUC generic ) ( Dose generic ) ( AUC Brand ) ( Dose Brand )
REV. 97.4.22
8-84
ug 47 ------ mL hr 500 mg CB = -------------------------------------------------------- = 0.94 ug 50 ------ mL hr 500 mg

14. Bioequivalent: Yes if all three = Yes:
0.80 < CB < 1.25 CB = 0.94 = Yes t p gen eric t p gen eric 2.15 hr - < 1.25 ------------- = --------------- = 1.44 = NO 0.80 < ------------t p b ra nd t p b ra nd 1.49 hr ug 7.4 ------C p max gen eric mL ----------------------- = --------------- = 0.77 = NO C p max b rand ug 9.6 ------mL
C p max gen eric - < 1.25 0.80 < ----------------------C p ma x b rand
REV. 97.4.22
8-85
8.7.3
CEFIXIME ON PAGE 63
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a washout period between the administration of each dosage form. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1)
IV 200 47
Bioequivalence
183.3
162.8
187.5
3.9 0.256
6.9 3.0
9.3 5.38
ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 12.1 12.1
0.334
0.186
16.6 9.3 1.5 0.77
0.50 2.5
0.43 1.6 0.64
3.4
4.6
1.33 0.86 NO
REV. 97.4.22
8-86
8.7.4
CEFTIBUTEN ON PAGE 64
"The pharmacokinetics of ceftibuten in humans"
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram positive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus dose of ceftibuten. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
IV 200 75.2
Bioequivalence
211.2
213.4
220
208
2.94 0.390
3.24 0.297
3.43 0.485
3.25 0.309
3.37 25.6
2.06
3.24
7.8 18.2 16.9 15.3 16.4
0.44 25.6 17.3
0.42 15.3
0.43 16.7 1.09
0.76
1.05
0.78
0.74 1 NO
REV. 97.4.22
8-87
8.7.5
CIMETIDINE ON PAGE 65
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Journal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer disease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained from this experiment is given below.
IV 300 3.81
Bioequivalence
5.33
11.73
10.73
1.40 0.715
4.73 3.33
4.29 2.89
0.300
0.346
110 1.33 0.32 0.37
0.65 0.40
0.66 0.44 1.1
2.1
2.0
0.94 1 YES
REV. 97.4.22
8-88
8.7.6
DIURNAL VARIABILITY IN THEOPHYLLINE BIOAVAILABILITY ON PAGE 66
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Pharmacokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data obtained from this experiment for the time period between midnight and noon is given below. From the preceding data, please calculate the following:
IV 500 160.25
Bioequivalence
1821
1662
1785
1700
11.40 0.088
11.50 0.13
12.75 1.39
11.8 0.44
7.58
0.721
2.26
35.5 12.9 11.8 6.02 10.7
0.90 12.1
0.87 9.20
0.90 11.1 1.21
.059
3.3
1.5
0.45 1.03 NO
REV. 97.4.22
8-89
8.7.7
CIS-5-FLUORO-1-[2-HYDROXYMETHYL-1,3-OXATHIOLAN-5-YL] CYTOSINE (FTC) ON PAGE 67
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Antimicrobial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2,3-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1)
IV 100 265
Bioequivalence
19514
12600
13125
73.6 .0136
75 1.36
75 1.36
ka (hr-1) ug Cp0 ------ mL Vd (L/kg) ug Cp at 1 hour ------ mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 3.6 3.6
0.734
0.734
27.7 3.55 1.18 1.23
0.63 2.1
0.66 2.2 1.04
5.54
5.54
1.0 1.04 YES
REV. 97.4.22
8-90
8.7.8
HYDROMORPHONE ON PAGE 68
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydromorphone on separate days. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) ug - hr AUC ----L ug - hr 2 AUMC ----L MRT (hr) MAT (hr) ke (hr-1)
IV 2 83
Brand Tablet 4 87.2
Generic Tablet 4 96
Bioequivalence
289.4
401
432
3.49 0.287
4.60 1.11
4.50 1.03
ka (hr-1) ug Cp0 ----L Vd (L) ug Cp at 1 hour ----L f ug Cpmax ----L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 23.8 23.8
0.899
0.987
84 17.9 12.6 14.7
0.53 14.6
0.56 16.6 1.13
1.87
1.77
0.95 1.1 YES
REV. 97.4.22
8-91
8.7.9
ISOSORBIDE DINITRATE ON PAGE 69
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Therapeutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure. In this study volunteers received a 5 mg intravenous dose and a 10 mg tablet. The different dosage forms were separated by a washout period. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ug - hr AUC ----L ug - hr 2 AUMC ----L MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ----L Vd (L) ug Cp at 1 hour ----L f ug Cpmax ----L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 5 370.3
Brand Tablet 10 158
Bioequivalence
487
310
305
1.32 0.760
1.96 0.65
1.85 0.53
1.546 282
1.875
17.75 132 60.1 66.2
0.21 282 60.4
0.22 67.8 1.12
0.90
0.81
0.90 1.04 YES
REV. 97.4.22
8-92
8.7.10
KETANSERIN ON PAGE 70
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28, (1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ng - hr AUC ------ mL ng - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------mL Vd (L) ng Cp at 1 hour ------mL f ng Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 10 541
Bioequivalence
11700
24900
22900
21.6 0.0402
22.1 0.5
22.0 0.4
2.0 25.0
2.5
400 23.9 43.6 42.7
.052 25.0 47.6
0.48 44.5 0.94
1.93
1.63
0.84 0.92 YES
REV. 97.4.22
8-93
8.7.11
METHOTREXATE ON PAGE 71
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis", British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The importance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis. Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as a 15 mg dose. The following data was obtained: From the preceding data, please calculate the following:
Parameter Dose (mg) nmole - hr AUC -------------- L nmole - hr 2 AUMC -------------- L MRT (hr) MAT (hr) ke (hr-1)
IV 15 2752
Bioequivalence
15887
18400
18500
5.77 0.173
6.79 1.02
6.85 1.08
ka (hr-1) nmole Cp0 -------------- L Vd (L) nmole Cp at 1 hour -------------- L f nmole Cpmax -------------- L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 477 477
0.979
0.927
69.3 401 265 256
0.98 323
0.98 318 0.98
2.15
2.23
1.04 1.0 YES
REV. 97.4.22
8-94
8.7.12
MOCLOBEMIDE ON PAGE 72
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Journal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------mL Vd (L) ug Cp at 1 hour ------mL f ug Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 150 2.58
Bioequivalence
6.35
5.91
5.90
2.46 0.406
3.48 1.02
3.80 1.42
0.985 1.05
0.704
143 0.698 0.344 0.250
.099 1.05 .037
.088 0.29 .079
1.53
1.85
1.21 0.89 NO
REV. 97.4.22
8-95
8.7.13
NALBUPHINE ON PAGE 73
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study, volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ng - hr AUC ------ mL ng - hr 2 AUMC ------mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------ mL Vd (L) ng Cp at 1 hour ------ mL f ng Cpmax ------mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 10 86.9
Bioequivalence
288
306
280
270
3.31 .0301
4.35 1.04
4.48 1.17
4.5 1.19
0.963 26.2
0.858
0.843
381 19.4 11.1 9.2 8.7
0.180 26.2 12.5
0.180 10.7
0.173 10.2 0.95
1.76
1.88
1.90
1.01 0.96 YES
REV. 97.4.22
8-96
8.7.14
NEFAZODONE ON PAGE 74
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg/kg) ng - hr AUC ------ mL ng - hr 2 AUMC ------mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------ mL Vd (L) ng Cp at 1 hour ------ mL f ng Cpmax ------mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 10 6023
Oral Solution 10 829
Brand Tablet 10 800
Bioequivalence
29283
4875
4800
4500
4.86 0.210
5.88 1.02
6.0 1.14
6.43 1.57
0.982 1238
0.879
0.638
8.07 1009 94.8 85.7 60.7
0.138 1238 112.7
0.133 105.6
0.116 84.0 0.80
2.0
2.16
2.62
1.21 0.88 YES
REV. 97.4.22
8-97
8.7.15
ONDANSETRON ON PAGE 75
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Pharmaceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailability of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) ng - hr AUC ------ mL ng - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1)
IV 8 246.5
Brand Tablet 8 139
Bioequivalence
1138
795
870
4.62 0.217
5.72 1.10
6.0 1.38
ka (hr-1) ng Cp0 ------mL Vd (L) ng Cp at 1 hour ------mL f ng Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 53.4 53.4
0.907
0.723
150 43 15.9 14.7
0.56 19.2
0.59 18.8
2.1
2.4
1.1 1.04 YES
REV. 97.4.22
8-98
8.7.16
OMEPRAZOLE ON PAGE 76
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Pharmacology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) mole - hr AUC -------------- L mole - hr 2 AUMC -------------- L MRT (hr) MAT (hr) ke (hr-1)
IV 20 3.2
Bioequivalence
3.2
5.25
4.5
1.0 1
1.5 0.5
1.5 0.5
ka (hr-1) mole Cp0 -------------- L Vd (L) mole Cp at 1 hour -------------- L f mole Cpmax -------------- L Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No) 3.2 3.2
52.4 1.18 1.63 1.40
0.55 1.8
0.47 1.5 0.86
0.69
0.69
1 0.86 YES
REV. 97.4.22
8-99
8.7.17
PAROXETINE ON PAGE 77
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg and slow intravenous infusion of 28 mg. A summary of the some of data obtained from this experiment is given below.
Parameter Dose (mg) ng ------AUC mL hr ng 2 ------AUMC mL hr MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------mL Vd (L) ng Cp at 1 hour ------mL f ng ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 28 467
Brand Tablet 45 750
Bioequivalence
6671
11250
10463
14.3 0.07
15 0.72
15.5 1.22
1.40 32.7
.082
856 30.5 37.9 25.5
1 32.7 44.8
0.90 37.6 0.84
2.25
3.27
1.45 0.90 NO
REV. 97.4.22
8-100
8.7.18
RANITIDINE ON PAGE 78
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986), p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ng - hr AUC ------ mL ng - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ng Cp0 ------mL Vd (L) ng Cp at 1 hour ------mL f ng Cpmax ------ mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 50 5159
Bioequivalence
53415
78752
84413
10.4 0.0966
12.3 1.91
12.5 2.15
0.524 498
0.466
100 452 240 231
.0415 498 423
0.436 432 1.02
3.96
4.26
1.07 1.05 YES
REV. 97.4.22
8-101
8.7.19
SULPIRIDE ON PAGE 79
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups. The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary of the some of data obtained from this experiment is given below. From the preceding data, please calculate the following:
Parameter Dose (mg) ug - hr AUC ------ mL ug - hr 2 AUMC ------mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0 ------ mL Vd (L) ug Cp at 1 hour ------ mL f ug Cpmax ------mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV 100 8.27
Bioequivalence
79.1
87.3
91.1
84.5
9.56 0.865
9.93 0.367
10.6 1.02
10.6 1.0
2.72 0.865
0.972
1.0
116 0.779 0.798 0.526 0.498
0.53 0.865 0.807
0.52 0.687
0.48 0.643 0.94
1.24
2.57
2.52
0.98 0.93 YES
REV. 97.4.22
8-102
8.8 References
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Parameter Dose (mg/kg) ug - hr AUC ------ mL ug - hr 2 AUMC ------ mL MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) T1/2 elim (hr) T1/2 abs (hr) ug Cp0 ------mL Vd (L) ug Cp at 1 hour ------mL ug - hr AUC0-1 ------ mL f ug ------Cpmax mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)
IV
Oral Solution
Brand Tablet
Generic Tablet
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CHAPTER 8

Bioavailability, Bioequivalence, and Drug Selection

Author: Rasma Chereson Reviewer: Umesh Banakar

Bioavailability, Bioequivalence, and Drug Selection

8.1 Bioavailability, Bioequivalence and Drug Product Selection

RELATIVE AND ABSOLUTE BIOAVAILABILITY

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

for Absolute and Relative Bioavailability

FACTORS INFLUENCING BIOAVAILABILITY

Bioavailability, Bioequivalence, and Drug Selection

Factors related to the dosage form

TABLE 8-3. Bioavailability

Factors Related to the patient

Interactions with other substances Food Fluid volume Other drugs

Bioavailability, Bioequivalence, and Drug Selection

and oral Dosage Forms

Solutions Suspensions Capsules Tablets Coated tablets

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Factors influencing Gastric Emptying Rate

INFLUENCE ON GASTRIC EMPTYING RATE

increased or decreased decreased increased decreased

Bioavailability, Bioequivalence, and Drug Selection

Effect of Food on Drug Absorption

Bioavailability, Bioequivalence, and Drug Selection

Drug interactions affecting absorption

Bioavailability, Bioequivalence, and Drug Selection

METHODS OF ASSESSING BIOAVAILABILITY

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

dose vs. single dose studies in bioavailability studies

Bioavailability, Bioequivalence, and Drug Selection

IN-VITRO DISSOLUTION AND BIOAVAILABILITY

Bioavailability, Bioequivalence, and Drug Selection

Official dissolution tests -

Limitations of dissolution tests-

Bioavailability, Bioequivalence, and Drug Selection

Device factors affecting dissolution

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

TABLE 8-10. Drugs

with various risk potential for inequivalence

Bioavailability, Bioequivalence, and Drug Selection

provisions for bioavailabilty regulations

Criteria for establishing a bioequivalence requirement -

Bioavailability, Bioequivalence, and Drug Selection

Pharmacokinetic evidence of any of the following:

Types of Bioequivalence Requirements

Bioavailability, Bioequivalence, and Drug Selection

Criteria for waiver of evidence of in-vivo bioavailability -

Bioavailability, Bioequivalence, and Drug Selection

Provisions for bioequivalence requirements

Bioavailability, Bioequivalence, and Drug Selection

way cross over design

10 subjects per group

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection

Bioavailability, Bioequivalence, and Drug Selection