Therapeutic Drug Monitoring: Newer Drugs and Biomarkers

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Chapter 1

Introduction to Therapeutic Drug Monitoring

Frequently and Less Frequently Monitored Drugs

Amitava Dasgupta

Department of Pathology and Laboratory Medicine, University of Texas-Houston, Houston, TX

Outline

Introduction

Drugs that Require Therapeutic Drug Monitoring

Benefits of Therapeutic Drug Monitoring

Pathophysiological Conditions and other Factors that Affect Drug Concentrations

Basic Pharmacokinetics

Genetic Variations in Drug Metabolism and Therapeutic Drug Monitoring

Effect of Gender Difference and Pregnancy on Drug Response and Metabolism

Effect of Age on Drug Response and Metabolism

Drug Disposition in Uremia

Drug Disposition in Hepatic Disease

Cardiovascular Disease and Drug Disposition

Thyroid Dysfunction and Drug Disposition

Therapeutic Drug Monitoring of Various Drug Classes

Frequently and Less Frequently Monitored Anticonvulsants

Frequently and Less Frequently Monitored Cardioactive Drugs

Frequently Monitored Anti-Asthmatic Drugs

Frequently and Less Frequently Monitored Antidepressants

Frequently Monitored Immunosuppressants

Frequently and Less Frequently Monitored Antibiotics

Less Frequently Monitored Drugs: Antiretroviral Agents

Frequently and Less Frequently Monitored Antineoplastic Drugs

Conclusions

Introduction

There are over 6000 prescription and non-prescription (often termed as over-the-counter) drugs approved by the FDA (Federal Drug Administration of the United States government) for clinical use. The spending for prescription drugs was US$234.1 billion in 2008, which was more than double the amount of money spent in 1999. The percentage of Americans who had used at least one prescription drug in the past month increased from 44% in 1999–2000 to 48% in 2007–2008, and, as expected, the percentage of Americans using five or more drugs also increased steadily during this period (Fig. 1.1). People aged over 60 years required more prescription drugs than younger people: only 7.9% of Americans between the ages of 20 and 59 used five or more drugs, but 36.7% of Americans aged over 60 years used five or more medications. The most commonly used drugs, based on drug use in the 2007–2008 survey, are as follows: children (age up to 11 years), bronchodilators; adolescents (12–19 years), central nervous system stimulants; adults (20–59 years), antidepressants; and elderly patients, cholesterol-lowering medications. The percentages of the most often used prescription drugs in various age groups of the American population are shown in Fig. 1.2. Diuretics and beta-blockers are also commonly used by adults and older Americans. People without a regular place for health care, health insurance, or prescription drug benefits had lower use of prescription drugs [1].

FIGURE 1.1 Trend in use of prescription drugs among Americans.

(Source: Reference 1: US Government Document).

FIGURE 1.2 Percentage of prescription drugs used most often in various age groups of American population.

(Source: Reference 1: US Government Document).

Many patients, especially the elderly, take drugs for controlling chronic conditions. Although none of the non-prescription drugs requires therapeutic drug monitoring, except for salicylate and acetaminophen in cases of overdose or attempted suicide, some prescription medications require routine therapeutic drug monitoring. Fortunately, the number of such drugs requiring routine monitoring is relatively low. Approximately 26 prescription drugs are frequently monitored in a majority of hospital-based laboratories using commercially available immunoassays and automated analyzers. In addition, approximately 25–30 drugs are subjected to therapeutic drug monitoring less frequently, and immunoassays are available for only a few such drugs. Therefore, chromatographic techniques are used for monitoring of these drugs, and such tests are only available in clinical laboratories of major medical centers and academic centers as well as reference laboratories. The most sophisticated method for therapeutic drug monitoring is liquid chromatography combined with mass spectrometry or tandem mass spectrometry (see Chapter 3 for a detailed discussion on this topic).

Therapeutic drug monitoring not only consists of measuring the concentration of a drug in a biological matrix but also involves the proper interpretation of the value using pharmacokinetic parameters, drawing appropriate conclusions regarding the drug concentration and dose adjustment. The International Association for Therapeutic Drug Monitoring and Clinical Toxicology adopted the following definition for drug monitoring [2]:

 Therapeutic drug monitoring is defined as the measurement made in the laboratory of a parameter that, with appropriate interpretation, will directly influence prescribing procedures. Commonly, the measurement is in a biological matrix of a prescribed xenobiotic, but it may also be of an endogenous compound prescribed as a replacement therapy in an individual who is physiologically or pathologically deficient in that compound.

Therapeutic drug monitoring has been used in clinical practice to individualize drug therapy since the beginning of the 1970s. The goal of such monitoring is to optimize the pharmacological responses of a drug while avoiding adverse effects. Traditionally, therapeutic drug monitoring involves measuring drug concentration in a biological matrix – most commonly serum or plasma – and interpreting these concentrations in terms of relevant clinical parameters. Whole blood is the preferred matrix for therapeutic drug monitoring of immunosuppressants except for mycophenolic acid. For success of a therapeutic drug monitoring program, good communication between clinicians, laboratory professionals and pharmacists is essential. In one report, the authors clearly documented that the intervention of pharmacists significantly improved the appropriateness of therapeutic drug monitoring use and significantly reduced unnecessary costs. In addition, the authors commented that using a screening checklist including the indication for therapeutic drug monitoring, specimen collection time and data needed for proper interpretation of the drug level can improve appropriateness of utilization of the therapeutic drug monitoring service [3].

Drugs that Require Therapeutic Drug Monitoring

As stated earlier, only a small fraction of prescription drugs require therapeutic drug monitoring because for most prescription drugs there is a wider difference between therapeutic and toxic concentrations. For example, the therapeutic range of acetaminophen found in many over-the-counter drugs is 10–30 μg/mL, while toxicity is encountered at serum or plasma concentrations over 200 μg/mL. Because of the more than six-fold difference between the upper end of the therapeutic and lower end of the toxic concentration, acetaminophen is not monitored except in the case of a suspected overdose. In contrast, the therapeutic range of phenytoin is 10–20 μ/mL while toxicity may be encountered at a concentration of 30 μg/mL. Genetic polymorphism can precipitate phenytoin toxicity after a therapeutic dose. Ramasamy et al. described a case where a female developed phenytoin toxicity after administration of a therapeutic dosage of 300 mg per day of phenytoin. Her serum phenytoin level was 33 μg/mL. She was homozygous for a CYP2C9∗3∗3 mutation that led to a marked decrease in enzymatic activity of CYP2C9, which is responsible for metabolism of phenytoin [4]. Situations where therapeutic drug monitoring is beneficial include the following:

1. Where there is difficulty in interpreting therapeutic or low toxicity levels of a drug based on clinical evidence alone and there is no clearly defined clinical parameter for dose adjustment.

2. Where correlation between serum or whole blood drug concentration and dosage is poor.

3. Where there is a narrow therapeutic range, so the dose of a drug which produces the desired therapeutic concentrations in one patient may cause toxicity in another patient.

4. Where toxicity of a drug may lead to hospitalization, irreversible organ damage and even death, but an adverse drug reaction may be avoided by therapeutic drug monitoring.

5. Where there is a correlation between serum or whole blood concentration of the drug and its therapeutic response or toxicity.

6. Where there are clinical indications for therapeutic drug monitoring – for example, poor response to the drug, suspected treatment failure due to non-compliance, or signs of toxicity despite no dosage adjustment.

For strongly protein-bound drugs (protein binding > 80%), a better correlation may be observed between unbound (free) drug concentration (rather than traditionally monitored total drug concentration) and clinical outcome, because it is only the unbound drug that is responsible for the drug’s pharmacological action. For example, adjusting phenytoin dosage in patients based on their serum phenytoin concentrations rather than seizure frequencies not only decreases morbidity but also prevents phenytoin toxicity in these patients. Peterson et al. reported that, in their study involving 114 patients, free phenytoin concentrations correlated better with clinical picture than did total phenytoin concentrations [5] (see Chapter 4 for further details).

Usually, anticonvulsants, cardioactive drugs, immunosuppressants, anti-asthmatic drugs, antidepressants, antiretroviral drugs, antineoplastic drugs and antibiotics with narrow therapeutic windows, such as vancomycin and aminoglycosides, require routine therapeutic drug monitoring. In most instances the trough blood level (15–30 minutes prior to the next dosage) is the preferred specimen for therapeutic drug monitoring except for certain antibiotics (vancomycin and aminoglycosides), where both peak and trough drug levels are monitored. Vancomycin and aminoglycoside can produce serious nephrotoxicity and ototoxicity. Suggested therapeutic ranges for commonly monitored drugs as well as less commonly monitored drugs are listed in Table 1.1.

TABLE 1.1 Frequently and Less Frequently Monitored Therapeutic Drugs

Therapeutic ranges based on published literature, books as well as ranges adopted by reputed national reference laboratories such as Mayo Medical Laboratories and ARUP laboratories. However, therapeutic ranges vary widely among different patient populations and each institute should establish their own guidelines. These values are for the purpose of providing examples only.

∗ Monitored in whole blood instead of serum or plasma.

# Reference range recommend by the ARUP reference laboratory, Salt Lake City, UT.

Benefits of Therapeutic Drug Monitoring

Benefits of therapeutic drug monitoring are listed in Table 1.2. In general, many drugs are used as a prophylactic to prevent clinical symptoms – for example, phenytoin is given to a patient in order to prevent an episode of seizure. However, non-compliance has serious clinical consequences, and therapeutic drug monitoring is very useful in identifying such non-compliance. Mattson et al. commented that a zero drug level, subtherapeutic levels or variable drug levels are indicators of non-compliance in a medication where therapeutic drug monitoring is available. In the authors’ experience, 93% of their patients showed good adherence to the treatment protocol, as determined by therapeutic drug monitoring [6]. In contrast, in another report the authors used routine therapeutic drug monitoring to study compliance with theophylline and phenytoin therapy in a group of 80 outpatients and observed that only 37% of patients studied were complaint. The most interesting finding by the authors was that approximately half of the non-compliant patients were unaware of the necessity for taking their medication on a continuous basis [7]. Chandra et al. commented that poor patient compliance is one of the major causes of non-responsiveness to anti-epileptic drug therapy. Compliance is mostly assessed by self-reporting, therapeutic drug monitoring and pill-counting, but therapeutic drug monitoring is superior to other approaches for determining patient compliance with therapy. The authors determined that an adult patient receiving a dosage of 300 mg or more of phenytoin a day and showing plasma phenytoin levels of less than 5 μg/mL should be investigated for potential non-compliance [8]. Reis et al. determined partial compliance with sertraline therapy in depressed patients by determining plasma levels of sertraline and its metabolite [9]. Stieffenhofer and Hiemke commented that lack of or an insufficient response to a drug may be due to non-compliance of the patient or reduced absorption of the drug, or to ultra-rapid metabolism of the drug due to the genetic makeup of the patient. Therefore, to identify the reason(s) for a poor response to a drug, suboptimal plasma concentrations should be investigated further to identify non-compliance of a patient and pharmacogenetic testing considered in order to identify a rapid metabolizer [10].

TABLE 1.2 Benefits of Therapeutic Drug Monitoring (TDM)

Other than non-compliance, a patient’s response to a particular drug depends on many factors, including bioavailability, drug clearance, drug protein binding and the pathophysiological condition of the patient, as well as many other factors such as whether the medication is taken with food, whether the patient is a smoker, etc. The genetic makeup of an individual is also very important in determining whether a person will respond to a particular drug and how well the drug, if effective, exerts its pharmacological action. Pharmacotherapy could in many cases be ineffective, because as many as 30–60% of patients may be non-responders to a particular drug due to these factors [11]. Therapeutic drug monitoring can greatly reduce the chance of treatment failure by personalizing the drug dosage based on the results of therapeutic drug monitoring. Personalized drug therapy based on the genetic makeup of a patient has gained importance in the past decade, especially since the complete characterization of the human genome. This topic is addressed in Chapter 6. In addition, life-threatening adverse drug reactions are responsible for 6–7% of all hospitalization in the US and account for over 100 000 deaths annually [12]. Therapeutic drug monitoring helps to avoid adverse drug reactions due to drug–drug interaction and can also reduce the toxicity of an individual drug where therapeutic drug monitoring is available. Billaud et al. reported a case of a 54-year-old male renal transplant recipient who received antifungal treatment in combination with the immunosuppressant drug everolimus in order to prevent post-transplant reactivation of aspergillosis. Voriconazole was withdrawn after 1 month due to elevated trough concentrations (5  mg/L) and hepatotoxicity, and posaconazole was substituted. However, both voriconazole and posaconazole interacted with everolimus, causing 7.5- and 3.8-fold increases in the trough everolimus level, respectively, due to inhibition of everolimus metabolism by CYP3A4. The authors were successful in avoiding drug toxicity by careful therapeutic drug monitoring of both the antifungal drug and everolimus, and subsequent dosage adjustment to keep the everolimus concentration within the therapeutic range [13]. Gulbis et al. described a clinically significant drug interaction between busulfan and metronidazole where an adverse reaction was avoided by therapeutic drug monitoring of busulfan. A 7-year-old boy with a history of myelodysplasias that progressed to myeloid leukemia was treated with busulfan, clofarabine and thiotepa as a pretransplant conditioning regime for a cord blood transplant, and after receiving metronidazole his clearance of busulfan decreased by 46% as determined by therapeutic drug monitoring of busulfan. Busulfan was eventually discontinued to avoid drug toxicity [14].

Therapeutic drug monitoring is useful in minimizing adverse drug effects due to drug toxicity. In one report, the authors concluded that therapeutic drug monitoring in pain management using opioids can minimize adverse drug events while maximizing efficacy of the therapy [15]. Patel et al. studied the benefits of therapeutic drug monitoring of olanzapine in 3207 patients and observed that in patients aged 17 years or younger, median plasma olanzapine was higher than in adult patients at all olanzapine dosages. In addition, smoking status, age, sex and body weight together explained 24% of the variance in plasma olanzapine concentrations. The degree of adherence, drug–drug interactions and pharmacogenetic factors also contributed to wide variance in the olanzapine drug level in plasma specimens. Interestingly, female non-smokers had higher plasma olanzapine concentrations for a given dosage than did male smokers. The authors concluded that therapeutic drug monitoring of olanzapine may have a role in limiting olanzapine dosage to minimize the risk of long-term toxicity [16]. Slaughter et al. reported that therapeutic drug monitoring of aminoglycoside can significantly reduce incidences of nephrotoxicity from therapy with aminoglycosides. The authors further concluded that, from the pharmacoeconomic point of view, therapeutic drug monitoring of aminoglycosides is beneficial because therapeutic drug monitoring for an individual patient during therapy cost approximately US$301 while each case of nephrotoxicity cost the hospital US$4583 [17]. Crist et al. evaluated the impact of therapeutic drug monitoring of aminoglycoside (gentamicin and tobramycin) in 221 patients on the length of hospital stay, cost-effectiveness and related factors. The mean length of hospital stay was 8.4 days in the patient group that received individualized aminoglycoside doses (study group) versus 11.8 days in the control group. In addition, the hospital cost was lower by US$725 per patient in the study group, which would produce an annual saving of US$640 000 at the author’s institution [18]. In another report, the authors concluded that therapeutic drug monitoring of beta-lactam antibiotics in critically ill patients twice a week and dosage adjustments based on blood level resulted in prevention of drug toxicity and a positive outcome in 87.3% of the patients studied [19]. Reduced drug-related toxicities are not only beneficial for patients, but also diminish the liability of physicians and improve the quality of patient care as well as patient safety. Ried et al. evaluated the effectiveness of therapeutic drug monitoring in reducing toxic drug reactions by meta-analysis of 14 studies. The authors concluded that patients monitored for appropriate drugs suffered fewer toxic drug reactions than patients where therapeutic drug monitoring was not undertaken [20]. Another study reported that determination of serum drug concentrations and evaluation of such results by clinical pharmacists resulted in significant cost savings [21].

Routine therapeutic drug monitoring is also very useful in investigating non-response to a drug. Apart from non-compliance, various other factors may contribute to non-response to a drug. Muller et al. observed that patients not responding to the antipsychotic drug amisulpride had significantly lower plasma levels than patients who showed moderate improvement despite comparable dosage. Moreover, the daily amisulpride dosage did not predict non-response or response. The authors also established the optimal plasma concentration of amisulpride to avoid non-response to be 100 ng/mL. The authors concluded that therapeutic drug monitoring of amisulpride is very useful for clinical decision-making [22]. Babalik et al. commented that low levels of antituberculosis drugs may be responsible for a poor treatment outcome because monitoring of these drugs is not routinely performed. The authors studied 20 patients, and observed that the majority of them (17 patients) had at least one low serum level of an antituberculosis drug. The authors concluded that therapeutic drug monitoring is potentially useful in improving outcome when treating these patients [23]. Sometimes a higher serum drug level may be needed to achieve optimal therapeutic benefit from a drug in a particular ethnic group. Wang et al. reported that among Chinese patients with HIV infection the therapeutic trough concentration of nevirapine was 3.9 μg/mL – significantly higher than the recommended drug concentration of 3.0 μg/mL. The authors commented that the correlation between nevirapine concentrations and efficacy as well as hepatotoxicity suggests benefits of dosage adjustment of nevirapine based on therapeutic drug monitoring in Chinese patients infected with HIV in order to optimize antiretroviral therapy [24].

Pathophysiological Conditions and other Factors that Affect Drug Concentrations

The serum concentration of a particular drug is determined by absorption, distribution, metabolism and excretion of a drug. Major characteristics that affect serum drug concentrations include genetic makeup, pathophysiological condition and various other factors. Hepatic disease may alter the metabolism of a drug, where a patient with renal failure may clear a drug in urine more slowly than a patient with normal renal function. Pregnancy alters the metabolism of several drugs, while drug–drug interactions may also significantly alter serum drug concentrations.

Basic Pharmacokinetics

When a drug is administered orally it undergoes several steps in the body that determine the concentration of that drug in serum/plasma or whole blood. These steps include:

1. Liberation – the release of a drug from the dosage form (tablet, capsule, extended-release formulation).

2. Absorption – movement of the drug from the site of administration (for drugs taken orally) to the blood circulation. Many factors affect this stage, including gastric pH and presence of food particles, as well as the efflux mechanism if present in the gut. First-pass metabolism plays an important role in determining the bioavailability of a drug given orally.

3. Distribution and protein binding – movement of a drug from the blood circulation to tissues/target organs. Drugs may also be bound to serum proteins, ranging from no protein binding to 99% protein binding.

4. Metabolism – chemical transformation of a drug to the active and inactive metabolites. The liver is responsible for metabolism of many drugs, although drugs may also be metabolized by a non-hepatic path or be subjected to minimal metabolism.

5. Excretion – elimination of the drug from the body via renal, biliary or pulmonary mechanisms.

Basic pharmacokinetics is discussed in detail in pharmacology textbooks, and therefore only a brief discussion of this important topic is presented in this chapter. Liberation of a drug after oral administration depends on the formulation of the dosage. An immediate-release formulation releases the drugs at once from the dosage form when administered, while the same drug may also be available in a sustained-release formulation. Absorption of a drug depends on the route of administration. Generally oral administration is the route of choice, but under certain circumstances (nausea, vomiting and convulsions) the rectal route may present a practical alternative for delivering anticonvulsants, non-narcotic and narcotic analgesics, theophylline, and antibacterial and anti-emetic agents. This route can also be used for inducing anesthesia in children. Although the rate of drug absorption is usually lower after rectal administration compared to oral administration, for certain drugs rectal absorption is higher compared to oral absorption due to avoidance of the hepatic first-pass metabolism. These drugs include lidocaine, morphine, metoclopramide, ergotamine and propranolol. Local irritation is a possible complication of rectal drug delivery [25]. When a drug is administered by direct injection, it enters the blood circulation immediately.

When a drug enters the blood circulation it is distributed throughout the body into various tissues, and the pharmacokinetic parameter is called the volume of distribution (Vd). This is the hypothetical volume to account for all drugs in the body, and is also termed the apparent volume of distribution:

The amount of a drug that interacts with the receptor or target site is usually a small fraction of the total drug administered. Muscle and fat tissues may serve as a reservoir for lipophilic drugs. For neurotherapeutics, penetration of the blood–brain barrier is essential. Drugs usually undergo chemical transformation (metabolism) before elimination. Drug metabolism may occur in any tissue, including the blood – for example, plasma butylcholinesterase metabolizes drugs such as succinylcholine. The role of metabolism is to convert lipophilic non-polar molecules to water-soluble polar compounds for excretion in urine. Many drugs are metabolized in the liver in two phases by various enzymes, but cytochrome P450, a mixed function oxidase, is the major liver enzyme responsible for the metabolism of a majority of drugs in the Phase I step that involves manipulation of a functional group of a drug molecule in order to make the molecule more polar. The Phase II step may involve acetylation, sulfation, methylation, amino acid conjugation or glucuronidation in order to increase the polarity of the drug metabolite.

The half-life of a drug is the time required for the serum concentration to be reduced by 50%. The fraction of a drug remaining in the body after five half-lives is approximately 0.03% for administration of a single dosage of the drug, while for repeated dosages of a drug a steady state is reached after five to seven half-lives. Therapeutic drug monitoring is recommended when a drug reaches a steady state. The half-life of a drug can be calculated from the elimination rate constant (K) of a drug:

The elimination rate constant can be easily calculated from the serum concentrations of a drug at two different time points using the formula

where Ct1 is the concentration of drug at time point t1 and Ct2 is the concentration of the same drug at a later time point t2.

A drug may also undergo extensive metabolism before fully entering the blood circulation. This process is called first-pass metabolism. If a drug undergoes significant first-pass metabolism, then the drug may not be delivered orally – for example, lidocaine. Renal excretion is a major pathway for the elimination of drugs and their metabolites; therefore impaired renal function may cause accumulation of drugs and metabolites in serum, thus increasing the risk of adverse drug effects. Moreover, other pathological conditions such as liver disease, congestive heart failure and hypothyroidism may also decrease the clearance of drugs. Drugs may also be excreted via other routes, such as via the biliary tract. The factors which determine biliary elimination of a drug include chemical structure, polarity and molecular weight, as well as active transport sites within the liver cell membranes for that particular drug. A drug excreted in bile may also be reabsorbed from the gastrointestinal tract or a drug conjugate may be hydrolyzed by the bacteria of the gut, liberating the original drug, which can return to the blood circulation. Enterohepatic circulation may prolong the effects of a drug. Cholestatic disease, where normal bile flow is reduced, may reduce bile clearance of the drug, causing drug toxicity.

Genetic Variations in Drug Metabolism and Therapeutic Drug Monitoring

Genetic differences between patients may significantly alter drug metabolism. Drugs are metabolized by various enzymes in the body, including serum butylcholinesterase, thiopurine methyltransferase and N-acetyltransferase, but, most notably, by liver cytochrome P450 mixed-function oxidase, also known as the cytochrome P450 family of drug-metabolizing enzymes. The cytochrome P450 proteins (CYPs) comprise a large group of heme-containing monooxygenase proteins that are localized to the endoplasmic reticulum and mitochondrial membrane. NADPH (nicotinamide adenine dinucleotide phosphate) is a required cofactor for CYP-mediated biotransformation, and oxygen serves as a substrate. The CYP superfamily is found in many organisms, with over 7700 known members across all species studied. At present, 57 human genes are known to encode CYP isoforms; of these, at least 15 are associated with xenobiotic metabolism. The major CYP isoforms responsible for metabolism of drugs include CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/CYP3A5. However, CYP3A4 is the predominant isoform of the CYP family (almost 30%) usually responsible for the metabolism of approximately 37% of drugs, followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%) and CYP2B6 (4%). In addition to liver, CYP3A4 isoenzyme is also present in significant amounts in the epithelium of the gut. Therefore, orally administered drugs which are substrates of CYP3A4 may undergo significant metabolism before entering circulation. Examples of representative drugs that are metabolized by various isoforms of the cytochrome P450 family of enzymes are given in Table 1.3. These cytochrome enzymes show marked variation in different people. Some of these enzymes also exhibit genetic polymorphism (CYP2C19, CYP2D6), and a subset of the population may be deficient in enzyme activity (poor metabolizers). Therefore, if a drug is administered to a patient who is a poor metabolizer, drug toxicity may be observed even with a standard dose of the drug. Mutation of CYP2D6 affects the analgesic effect of codeine and tramadol [26]. Knowledge of the polymorphism of various cytochrome P450 enzymes is important for the management of patients receiving various anticancer drugs, including tamoxifen, docetaxel, paclitaxel, cyclophosphamide, ifosfamide, imatinib, irinotecan, etoposide, teniposide, thalidomide and vincristine [27].

TABLE 1.3 Example of Representative Drugs that are Metabolized by Various Isoforms of the Cytochrome P450 Family of Enzymes

∗ Isoform represents highest amount of isoform in the cytochrome P450 family of drug-metabolizing enzymes and responsible for metabolism of majority of drugs metabolized via the cytochrome P450 family of enzymes.

Therapeutic drug monitoring is a phenotyping procedure and can be used to identify slow as well as fast metabolizers. However, a superior approach is pharmacogenomics testing, which is based on the utilization of genetic information data in pharmacotherapy and drug delivery, thus ensuring better drug efficacy and safety in patient management. The AmpliChip CYP450, which is capable of genotyping cytochrome P450 (CYP2D6 and CYP2C19) and predicts phenotypes for 27 CYP2D6 alleles, is the first FDA approved pharmacogenomics test [28]. This important topic is addressed in Chapter 6.

Effect of Gender Difference and Pregnancy on Drug Response and Metabolism

Men and women may show both pharmacokinetic and pharmacodynamic differences in response to certain drugs due to anatomical variation and different metabolism rates of specific drugs. Pregnancy may also significantly alter the disposition of a limited number of drugs. Gender difference affects bioavailability, distribution, metabolism and elimination of drugs due to variations between men and women in body weight, blood volume, gastric emptying time, drug protein binding, activities of drug-metabolizing enzymes, drug transporter function and excretion activity [29]. In general, the average male has higher bodyweight, greater body surface area and total water content (both extracellular and intracellular) compared to the average female, causing differences in volumes of distribution of certain drugs – most notably lipophilic drugs. Although absorption of a drug is not different between the two genders, the absorption rate may be slightly slower in females. Hepatic metabolism of drugs by Phase I (via CYP1A2 and CYP2E1) and Phase II (by glucuronyl transferase, methyltransferases and dehydrogenases) reactions appears to be faster in males than females, although metabolism of drugs by CYP2C9, CYP2C19 and N-acetyltransferase, or clearance of drugs which are substrates for P-glycoprotein, appear to be similar in both males and females. Women usually have higher activity of CYP3A4 [30]. Gallagher et al. reported gender difference in UDP-glucuronosyltransferase (UGT) activity, where men exhibited a fourfold higher level of expression of the UGT2B family of genes, especially UGT2B17, than women. Therefore, men have a higher amount of UGT2B17 glucuronidation activity than women, which may lead to significant gender variation in metabolism of steroid hormones, carcinogens, cancer chemotherapy agents and addictive agents found in cigarettes [31]. Women also have high levels of sex hormones, and may take oral contraceptives which usually contain progesterone alone or in combination with estrogen (natural or synthetic). Both natural and synthetic estrogens and progesterones (including common ethinyl estradiol) are metabolized by CYP3A4 and may affect metabolism of certain drugs. Ethinyl estradiol in combination with other components of oral contraceptive preparations can reduce serum lamotrigine concentration by 50% [32]. Soldin and Mattison reviewed sex differences in the pharmacokinetics and pharmacodynamics of many commonly used drugs [33].

In general, women are also more susceptible to adverse effects of than men. Women are at increased risk of QT prolongation with many anti-arrhythmic drugs, which may even lead to critical conditions such as torsade de pointes compared to men even at the same levels of serum drug concentrations [34]. Other classes of drugs that may cause more adverse drug reactions in women compared to men include anesthetics, and antiretrovirals. Hormonal effects may be one of the underlying causes in the majority of adverse drug reactions observed in women [35]. Women are also more vulnerable to drug abuse than men, and gonadal hormone estrogen may facilitate drug abuse in women. In addition, phases of the menstrual cycle when estrogen levels are high are associated with enhanced effects of both cocaine and amphetamine [36]. Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. Juul et al. observed that at a dosage of 100 μg the decrease in serum sodium was more significant in women aged over 50 than men, and recommended a lower dosage (25 μg) in women compared to men (50–100 μg) [37]. However, women gain a greater effect of analgesia in pain management from opioid analgesics [38]. In addition, certain psychotropic drugs such as chlorpromazine, fluspirilene and various antipsychotic drugs appear to be more effective in women than in men for the same dosage [39].

Epidemiologic surveys have indicated that between one-third and two-thirds of all pregnant women will take at least one medication during pregnancy. Drug therapy in pregnant women usually focuses on potential teratogenic effects of drugs, and therapeutic drug monitoring during pregnancy aims to improve individual dosage, taking into account pregnancy-related changes in drug disposition [40]. Gastrointestinal absorption and bioavailability of many drugs vary in pregnancy due to changes in gastric secretion and small intestine motility. In addition, various pregnancy-related hemodynamic changes, such as an increase in cardiac output, blood volume, renal perfusion and glomerular filtration rate, may affect drug disposition and elimination of several drugs [41]. Elevated concentrations of various hormones in pregnancy, such as estrogen, progesterone, placental growth hormone and prolactin, could be related to altered drug metabolism observed in pregnant women [42]. The renal excretion of unchanged drugs is increased in pregnancy. In addition, the metabolism of drugs catalyzed by isoenzymes of cytochrome P450 (CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT1A4 and UFT2B7) are increased in pregnancy. Therefore, dosages of drugs that are metabolized by these enzymes may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, activities of some isoenzymes (CYP1A2 and CYP2C19) are reduced in pregnancy. Therefore, dosage reduction may be needed for drugs that are metabolized via these isoenzymes [43]. Increases in clearance of lamotrigine have been reported in pregnancy. Apparent clearance seems to increase steadily during pregnancy until it peaks at approximately week 32, when 330% increases in clearance from base line values can be observed [44]. Lower serum concentrations of lithium have been reported in pregnancy, and this may be related to an increase in the glomerular filtration rate. Reduced plasma concentration of both the antimalarial drug chloroquine and its active metabolite desethyl-chloroquine in pregnancy could compromise the curative efficacy and post-treatment prophylactic property of chloroquine in pregnant women [45]. In general, dosage adjustments are required for anticonvulsants, lithium, digoxin, certain beta blockers, ampicillin, cefuroxime and certain antidepressants in pregnant women. In addition, certain drugs such as tetracycline, antithyroid medications, coumarin anticoagulants, aspirin, indomethacin, opioids, barbiturates and phenothiazine may have unwanted effects in the fetus despite careful adjustment of maternal dosage of these drugs [46, 47]. Gender differences and the effect of pregnancy on metabolism of common drugs are listed in Table 1.4.

TABLE 1.4 Gender Differences in the Effects of Some Representative Drugs

Source of data: Soldin and Mattison [33].

Effect of Age on Drug Response and Metabolism

In the fetus CYP3A7 is the major hepatic enzyme of the cytochrome P450 family of enzymes, but CYP3A5 may also present at significant levels in half of children. However, in adults CYP3A4 is the major functional cytochrome P450 enzyme responsible for metabolism of many drugs. CYP1A1 is also present during organogenesis, while CYP2E1 may be present in some second-trimester fetuses. After birth, hepatic CYP2D6, CYP2C8/9 and CYP2C18/19 are activated. CYP1A2 becomes active during the fourth to fifth months after birth [48]. Neonates and infants have increased total body water to body fat ratio compared to adults, whereas the reverse is observed in elderly people. These factors may affect the volume of distribution of drugs depending on their lipophilic character. Moreover, altered plasma binding of drugs may be observed in both neonates and some elderly people due to low albumin, thus increasing the fraction of pharmacologically active free drug. In general, the drug-metabolizing capacity of liver enzymes is reduced in newborns, particularly in premature babies, but increases rapidly during the first few weeks and months of life to reach values which are generally higher than adult metabolizing rates and then decline with old age. Renal function at the time of birth is reduced by more than 50% compared with adults but then increases rapidly in the first 2–3 years of life; it does, however, start declining with advanced age. Oral clearance of lamotrigine, topiramate, levetiracetam, oxcarbazepine, gabapentin, tiagabine, zonisamide, vigabatrin and felbamate is significantly higher (by 20–120%) in children compared to adults, depending on the drug and the age distribution of the patients. On the other hand, clearance of these drugs is reduced (by 10–50%) in the elderly population compared to middle-aged adults [49]. Zakrzewski-Jakubiak et al. reported that elderly patients are at higher risk of adverse drug reactions because most elderly patients receive multiple drugs and thus have an increased risk of pharmacokinetic drug interactions. The authors demonstrated the utility of InterMED-Rx software, a new cytochrome P450-based software that is capable of identifying elderly patients who are at risk of pharmacokinetic drug interactions as well as facilitating interventions aimed at reducing adverse drug events [50].

Premature infants may also metabolize a drug differently to adults; for example, only unchanged theophylline and caffeine is found in the urine of premature neonates, indicating the oxidative pathways for theophylline metabolism. In contrast, in children and adults 3-methylxanthine and 1,3-dimethyl uric acid are the major metabolites of theophylline recovered in the urine [51].

Drug Disposition in Uremia

Renal disease causes impairment in the clearance of many drugs by the kidney. Correlations have been established between creatinine clearance and clearance of digoxin, lithium, procainamide, aminoglycoside and several other drugs, but creatinine clearance does not always predict renal excretion of all drugs. Moreover, elderly patients may have unrecognized renal impairment, and thus caution should be exercised when prescribing medications to these patients. Serum creatinine remains normal until the GFR (glomerular filtration rate) has fallen by at least 50%. Nearly half of older patients have normal serum creatinine but reduced renal function. Dose adjustments based on renal function are recommended for many medications in elderly patients, even for medications that exhibit large therapeutic windows [52]. Renal disease also causes impairment of drug protein binding because uremic toxins compete with drugs for binding to albumin. Such interaction leads to increases in pharmacologically active free drug concentration, especially for classical anticonvulsants such as phenytoin, carbamazepine and valproic acid. Therefore, monitoring of free phenytoin, free valproic acid and to some extent free carbamazepine is recommended in uremic patients in order to avoid drug toxicity [53]. However, chronic renal failure can also significantly reduce non-renal clearance of many drugs, and drugs that are metabolized by Phase II reactions and drug transporter proteins such as P-glycoprotein and organic anion transporting polypeptide. High amounts of circulating uremic toxins, cytokines and parathyroid hormones are probably responsible for such reductions in clearance of these drugs, thus increasing the possibility of adverse drug reactions in uremic patients [54]. Animal studies have demonstrated significant downregulation (40–85%) of hepatic and intestinal metabolism mediated by cytochrome P450 enzymes in chronic renal failure [55]. Nolin et al. demonstrated that in patients with uremia, non-renal clearance of fexofenadine can be decreased up to 63% compared to controls. Moreover, there was a 2.8-fold increase in the area under the plasma concentration curve of fexofenadine in uremic patients compared to healthy subjects used as the control group. However, clearance of midazolam was not affected, indicating that function of CYP3A4 was not altered in patients with uremia. The authors further observed that the changes in hepatocytes and enterocyte protein expression were consistent with reduced clearance of fexofenadine, which is cleared through the activity of drug transport protein [56].

Drug Disposition in Hepatic Disease

Liver dysfunction not only reduces clearance of a drug metabolized through hepatic enzymes or the biliary mechanism but also affects plasm protein binding due to reduced synthesis of albumin and other drug-binding proteins. Even mild to moderate hepatic disease may cause an unpredictable effect on drug metabolism. Portal-systemic shunting present in patients with advanced liver cirrhosis may cause a significant reduction in first-pass metabolism of high extraction drugs, thus increasing bioavailability as well as the risk of drug overdose and toxicity [57]. In addition, activities of several isoenzymes of cytochrome P450 enzymes (CYP1A1, CYP2C19 and CYP3A4/5) are reduced due to liver dysfunction while activities of other isoenzymes such as CYP2D6, CYP2C9 and CYP2E1 may not be affected significantly. Therefore, drugs that are metabolized by CYP1A1, CYP3A4/5 and CYP2C19 may show increased blood levels in patients with hepatic dysfunction requiring dosage adjustment in order to avoid toxicity [58]. Although the Phase I reaction involving cytochrome P450 enzymes may be impaired in liver disease the Phase II reaction (glucuronidation) seems to be affected to a lesser extent, although both Phase I and Phase II reactions in drug metabolism are substantially impaired in patients with advanced cirrhosis. At this point there is no universally accepted endogenous marker to access hepatic impairment and a semi-quantitative Child-Pugh score is frequently used to determine the severity of hepatic dysfunction and thus dosage adjustments, although there are limitations to this approach [57]. Non-alcoholic fatty liver disease is the most common chronic liver disease. This type of liver disease also affects the activity of drug metabolizing enzymes in the liver, with the potential to produce adverse drug reactions from standard dosage [59].

Mild to moderate hepatitis infection may also alter the clearance of drugs. Trotter et al. reported that the total mean tacrolimus dose in year one after transplant was lower by 39% in patients with hepatitis C compared to patients with no hepatitis C infection [60]. Zimmermann et al. reported that the oral dose clearance of sirolimus was significantly decreased in subjects with mild to moderate hepatic impairment compared to controls, and the authors stressed the need for careful monitoring of trough whole blood sirolimus concentrations in renal transplant recipients exhibiting mild to moderate hepatic impairment [61]. Wyles and Gerber reviewed the effect of hepatitis with hepatic dysfunction on antiretroviral therapy, especially HAART (highly active antiretroviral therapy) in patients suffering from AIDS, and commented that the dosage of protease inhibitors indinavir, lopinavir, ritonavir, amprenavir and atazanavir may require reduction in patients with liver disease although hepatic dysfunction does not affect pharmacokinetics of nucleoside-reverse transcriptase inhibitors (NRTI) because these drugs are not metabolized by liver enzymes [62]. Ho et al. reported two novel genetic variations in the promotor sequence of CYP2D6 gene 1822A→G and 1740C→T in patients infected with hepatitis C that are associated with a lower activity of the CYP2D6 enzyme which is responsible for the metabolism of many drugs. Therefore, patients infected with the hepatis C virus may be at risk of drug toxicity and adverse drug reactions from drugs that are metabolized via CYP2D6 [63].

Hypoalbuminemia is often observed in patients with hepatic dysfunction which impairs the protein binding of many drugs. Because free (unbound) drugs are responsible for pharmacological action, careful monitoring of free concentrations of strongly albumin-bound anti-epileptic drugs such as phenytoin, carbamazepine and valproic acid is recommended in patients with hepatic dysfunction in order to avoid drug toxicity [53] (see Chapter 4 for more detail).

Cardiovascular Disease and Drug Disposition

Cardiac failure is often associated with disturbances in cardiac output, influencing the extent and pattern of tissue perfusion, sodium and water metabolism and gastrointestinal motility that eventually may affect the absorption and disposition of many drugs. Hepatic elimination of drugs via oxidative Phase I metabolism is impaired in patients with congestive heart failure due to decreased blood supply in the liver [64]. Theophylline metabolism is reduced in patients with severe cardiac failure, and dose reduction is strongly recommended. Digoxin clearance is also decreased. Quinidine plasma level may also be high in these patients due to a lower volume of distribution [65]. Therefore, therapeutic drug monitoring is crucial in avoiding drug toxicity in these patients. Physiological changes in critically ill patients can significantly affect the pharmacokinetics of many drugs. These changes include absorption, distribution, metabolism and excretion of drugs in critically ill patients. Understanding these changes in pharmacokinetic parameters is essential for optimizing drug therapy in critically ill patients. Norgard and Prescott commented that genetic biomarkers may play an important role in predicting a heart-failure patient’s response to therapy, as well as susceptibility to an adverse drug reaction [66].

Thyroid Dysfunction and Drug Disposition

Patients with thyroid disease may have an altered drug disposition because thyroxine is a potent activator of the cytochrome P450 enzyme system. Therefore, lower levels of drugs may result from high thyroxine levels due to induction of the hepatic oxidative metabolism pathway. In contrast, hypothyroidism is associated with inhibition of hepatic oxidative metabolism of many drugs. Hypothyroidism also affects the metabolism of immunosuppressants. Haas et al. reported a case where a patient developed hypothyroidism 6 months after single lung transplantation and was admitted to the hospital for anuric renal failure. The patient showed a toxic blood level of tacrolimus, which was resolved with the initiation of thyroxine replacement therapy and dose reduction of tacrolimus [67]. Therapeutic drug monitoring of immunosuppressants can thus aid in avoiding such drug toxicity. Amiodarone is a potent anti-arrhythmic drug associated with thyroid dysfunction because, due to high iodine content, amiodarone inhibits 5-deiodinase activity. Although most patients treated with amiodarone remain euthyroid, amiodarone-induced thyrotoxicosis or amiodarone-induced hypothyroidism may occur depending on the iodine status of the patient as well as the history of prior thyroid disease. Screening for thyroid disease before amiodarone therapy and periodic monitoring of thyroid functions are recommended for patients treated with amiodarone [68]. Burk et al. reported that thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and efficacy of drugs that are substrates for it. In hypothyroidism, digoxin clearance was significantly reduced, whereas bioavailability, volume of distribution, half-life and protein binding were unaltered, as reported by these investigators [69].

Therapeutic Drug Monitoring of Various Drug Classes

Usually, the concentration of a therapeutic drug is measured in the serum or plasma. However, whole blood concentrations of immunosuppressant drugs such as cyclosporine and tacrolimus are usually measured for therapeutic drug monitoring. Obtaining blood for measurement of a drug during the absorption or the distribution phase may lead to misleading information. Moreover, in order to measure the peak concentration of a drug, timing of the sample should depend on the route of administration. After intravenous administration, the peak concentration of a drug may be achieved in a few minutes. The trough concentration is clinically defined as the serum drug concentration just prior to the next dose. Usually trough concentrations are monitored for most drugs, but for aminoglycosides and vancomycin both peak and trough concentrations are monitored. For a meaningful interpretation of a serum drug concentration, time of specimen collection should be noted along with the time and date of the last dose and route of administration of the drug. This is particularly important for aminoglycoside because without knowing the time of specimen collection, the serum drug concentration cannot be interpreted. Information needed for the proper interpretation of drug levels for the purpose of therapeutic drug monitoring is listed in Table