Principles of Drug Therapy in Patients with Reduced Kidney Function

Gary R. Matzke | Thomas D. Nolin

Reduced kidney function may occur in many situations, including chronic kidney disease (CKD) resulting from such disorders as diabetes mellitus, hypertension, and glomerulonephritis, as well as age-related falls in glomerular ltration rate (GFR). In adults, these conditions are associated with a high use of medications, making these patients particularly susceptible to the accumulation of a drug or its active or toxic metabolites. Clinicians must have a thorough understanding of the impact of reduced kidney function on drug disposition and the appropriate methods by which to individualize drug therapy as they strive to optimize the outcomes of their patients. Individualization of therapy for those agents that are predominantly (>70%) eliminated unchanged by the kidney can be accomplished with a proportional dose reduction or dosing interval prolongation based on the fractional reduction in GFR or its more commonly evaluated clinical counterparts, creatinine clearance (CLCr) and estimated GFR. However, because impaired kidney function is associated with progressive alterations in the bioavailability, plasma protein binding, distribution volume, and nonrenal clearance (i.e., metabolism and transport) of many drugs, a more complex adjustment scheme may be required for medications that are extensively metabolized by the liver or for which changes in protein binding and/or distribution volume have been noted. Patients with impaired kidney function may also respond to a given dose or serum concentration of a drug (e.g., phenytoin) differently from those with normal kidney function because of the physiologic and biochemical changes associated with progressive CKD. Using a sound understanding of basic pharmacokinetic principles, the characteristics of a drug, and the pathophysiologic alterations associated with impaired kidney function, clinicians can design individualized therapeutic regimens. This chapter describes the inuence of impaired kidney function resulting from CKD and, when information is available, from acute kidney injury (AKI) on drug absorption, distribution, metabolism, transport, and excretion. The chapter also provides a practical approach to drug dosage individualization for patients with reduced kidney function and those receiving continuous renal replacement therapy (CRRT), peritoneal dialysis, or hemodialysis.

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absorption. Several variables, including changes in gastrointestinal transit time, gastric pH, edema of the gastrointestinal tract, vomiting and diarrhea (frequently seen in those with stage 5 CKD), and concomitant administration of phosphate binders, have been associated with alterations in the absorption of some drugs, such as digoxin and many of the uoroquinolone antibiotics. The fraction of a drug that reaches the systemic circulation after oral versus intravenous administration (termed absolute bioavailability) is rarely altered in CKD patients. However, alterations in the peak concentration (Cmax) and in the time at which the peak concentration was attained (tmax) have been noted for a few drugs, suggesting that the rate, but not the extent of absorption is altered in CKD. Although the bioavailability of some drugs, such as furosemide or pindolol, is reported to be reduced, there are no consistent ndings in patients with CKD to indicate that absorption is impaired. However, an increase in bioavailability as the result of a decrease in metabolism during the drugs rst pass through the gastrointestinal tract and liver has been noted for some -blockers, dextropropoxyphene, and dihydrocodeine.

DRUG DISTRIBUTION
The volume of distribution (VD) of many drugs is signicantly altered in patients with stages 4 or 5 CKD (Table 38.1), and changes in patients with oliguric AKI have also been reported. These changes are predominantly the result of altered plasma protein or tissue binding or of volume expansion secondary to reduced renal sodium and water excretion. The plasma protein binding of acidic drugs, such as warfarin and phenytoin, is decreased in patients with CKD, possibly due to changes in the conformation of the binding sites, accumulation of endogenous inhibitors of binding, and decreased concentrations of albumin. In addition, the high concentrations of metabolites of some drugs that accumulate in CKD patients may interfere with the protein binding of the parent compound. The plasma concentration of the principal binding protein for several basic drug compounds, 1-acid glycoprotein, is increased in kidney transplant patients and in hemodialysis patients. For this reason, the unbound fraction of some basic drugs (e.g., quinidine) may be decreased, and as a result, the VD in these patients is decreased. The net effect of changes in protein binding is usually an alteration in the relationship between unbound and total drug concentrations, an effect

DRUG ABSORPTION
Little quantitative information exists about the inuence of reduced kidney function in CKD patients on drug

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Table 38.1 Volume of Distribution of Selected Drugs in Patients with Stage 5 CKD
Drug Amikacin Azlocillin Cefazolin Cefoxitin Cefuroxime Clobrate Dicloxacillin Digoxin Erythromycin Gentamicin Isoniazid Minoxidil Phenytoin Trimethoprim Vancomycin

Normal (L/kg) 0.20 0.21 0.13 0.16 0.20 0.14 0.08 7.3 0.57 0.20 0.6 2.6 0.64 1.36 0.64

Stage 5 CKD (L/kg) 0.29 0.28 0.17 0.26 0.26 0.24 0.18 4.0 1.09 0.32 0.8 4.9 1.4 1.83 0.85

Change from Normal (%) 45 33 31 63 30 71 125 -45 91 60 33 88 119 35 33

CKD, Chronic kidney disease.

frequently encountered with phenytoin. The increase in unbound fraction, to values as high as 20% to 25% from the normal of 10%, results in increased hepatic clearance and decreased total concentrations. Although the unbound concentration therapeutic range is unchanged, the therapeutic range for total phenytoin concentration is reduced to 4 to 10 mcg/mL (normal, 10 to 20 mcg/mL) as GFR falls. Therefore the maintenance of therapeutic unbound concentrations of 1 to 2 mcg/mL provides the best target for individualizing phenytoin therapy in patients with reduced kidney function, and the optimal approach to management relies on the measurement of unbound phenytoin serum concentrations. Altered tissue binding may also affect the apparent VD of a drug. For example, the distribution volume of digoxin is reported to be reduced by 30% to 50% in patients with severe CKD. This may be the result of competitive inhibition by endogenous or exogenous digoxin-like immunoreactive substances that bind to and inhibit membrane adenosine triphosphatase (ATPase). The absolute amount of digoxin bound to the tissue digoxin receptor is reduced, and the resultant serum digoxin concentration observed after the administration of any dose is greater than expected. Therefore in patients with CKD, a normal total drug concentration may be associated with either serious adverse reactions secondary to elevated unbound drug concentrations or subtherapeutic responses because of an increased plasma-to-tissue drug concentration ratio. Monitoring of unbound drug concentrations is suggested for drugs that have a narrow therapeutic range, those that are highly protein bound (>80%), and those with marked variability in the bound fraction (e.g., phenytoin, disopyramide).

DRUG METABOLISM AND TRANSPORT

Nonrenal clearance (CLNR) of drugs includes all routes of drug elimination outside the kidney. Several oxidative and conjugative enzymes and active transporters constitute the primary pathways of CLNR. Alterations in the function of

and interactions between metabolic enzymes and transporters can signicantly affect the pharmacokinetic disposition and, correspondingly, patient exposure to drugs that are cleared via nonrenal pathways. The relationship of CKD to cytochrome P450 (CYP)mediated metabolism (the major oxidative or phase I metabolic pathway) in the liver and other organs has been extensively reviewed and is quite varied. In rat models of end-stage renal disease (ESRD), protein expression in the liver of several CYP enzymes, including CYP3A1 and CYP3A2 (equivalent to human CYP3A4), is reduced by as much as 85%. CYP2C11 and CYP3A2 activity is also significantly reduced, but CYP1A1 activity is unchanged. Hepatic expression of the conjugative enzymes N-acetyltransferases (NATs) are also reduced, whereas uridine diphosphateglucuronosyltransferases (UGTs) are unchanged. CYP functional expression is also decreased in the intestine; CYP1A1 and CYP3A2 are reduced up to 40% and 70%, respectively. Similarly, functional expression of several intestinal and hepatic transporters is altered in experimental models of kidney disease. The expression and corresponding activities of the efux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are reduced by as much as 65% in the intestine, but the uptake transporter organic anion transporting polypeptide (OATP) is not affected. Conversely, in the liver, protein expression of P-gp, MRP2, and OATP is increased, unchanged, and decreased, respectively. In humans with kidney disease, the activities of CYPs appear to be relatively unaffected. It was previously reported that CYP3A4 activity was reduced, but recent data indicate that OATP uptake activity is reduced and thus the perceived changes in CYP3A4 activity were likely due to altered transporter activity, not an alteration in CYP activity. The reduction of CLNR of several drugs that exhibit overlapping CYP and transporter substrate specicity in patients with stages 4 or 5 CKD supports this premise (Table 38.2). These studies must be interpreted with caution, however, because concurrent drug intake, age, smoking status, and alcohol use were often not taken into consideration. Furthermore, pharmacogenetic variations in drug-metabolizing enzymes and transporters that may have been present in the individual before the onset of AKI or progression of CKD must be considered, if known. For these reasons, prediction of the effect of reduced kidney function on the metabolism and/ or transport of a particular drug is difcult, and a general quantitative strategy to adjust dosage regimens for drugs that undergo extensive nonrenal clearance has not yet been proposed. However, some qualitative insight may be gained if one knows which enzymes or transporters are involved in the clearance of the drug of interest and how those proteins are affected by a reduction in kidney function. The effect of CKD on the nonrenal clearance of a particular drug is difcult to predict, even for drugs within the same pharmacologic class. The reductions in CLNR for patients with CKD have frequently been noted to be proportional to the reductions in GFR. In the small number of studies that have evaluated CLNR in critically ill patients with AKI, residual CLNR was higher than in CKD patients with similar levels of CLCr, whether measured or estimated from the CockcroftGault equation. Because a patient with AKI may have a higher CLNR than does a CKD patient, the resultant plasma concentrations will be lower than expected, and possibly subtherapeutic, if classic CKD-derived dosage guidelines are followed.

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Table 38.2 Major Pathways of Nonrenal Drug Clearance and Selected Substrates
CLNR Pathway Selected Substrates Oxidative Enzymes CYP 1A2 2A6 2B6 2C8 2C9 Polycyclic aromatic hydrocarbons, caffeine, imipramine, theophylline Coumarin Nicotine, bupropion Retinoids, paclitaxel, repaglinide Celecoxib, diclofenac, urbiprofen, indomethacin, ibuprofen, losartan, phenytoin, tolbutamide, S-warfarin Diazepam, S-mephenytoin, omeprazole Codeine, debrisoquine, desipramine, dextromethorphan, uoxetine, paroxetine, duloxetine, nortriptyline, haloperidol, metoprolol, propranolol Ethanol, acetaminophen, chlorzoxazone, nitrosamines Alprazolam, midazolam, cyclosporine, tacrolimus, nifedipine, felodipine, diltiazem, verapamil, uconazole, ketoconazole, itraconazole, erythromycin, lovastatin, simvastatin, cisapride, terfenadine

2C19 2D6

2E1 3A4/5

Conjugative Enzymes UGT NAT Acetaminophen, morphine, lorazepam, oxazepam, naproxen, ketoprofen, irinotecan, bilirubin Dapsone, hydralazine, isoniazid, procainamide

Transporters OATP 1A2 1B1 1B3 2B1 P-gp MRP 2 3

Bile salts, statins, fexofenadine, methotrexate, digoxin, levooxacin Bile salts, statins, fexofenadine repaglinide, valsartan, olmesartan, irinotecan, bosentan Bile salts, statins, fexofenadine, telmisartan, valsartan, olmesartan, digoxin Statins, fexofenadine, glyburide Digoxin, fexofenadine, loperamide, irinotecan, doxorubicin, vinblastine, paclitaxel, erythromycin Methotrexate, etoposide, mitoxantrone, valsartan, olmesartan Methotrexate, fexofenadine

that is eliminated unchanged in individuals with normal kidney function, the intrarenal drug transport pathways, and the degree of functional impairment of each of these pathways. The primary renal transport systems of clinical importance with respect to drug excretion include the organic anionic transporters (OATs), organic cationic transporters (OCTs), and P-gp transporters. Diuretics, -lactam antibiotics, nonsteroidal antiinammatory drugs, and glucuronide drug metabolites are eliminated by the family of OAT transporters. The OCT transporters contribute to the secretion and excretion of cimetidine, famotidine, and quinidine. And the P-gp transport system in the kidney is involved in the secretion of cationic and hydrophobic drugs (e.g., digoxin, vinca alkaloids). The clearance of drugs that are secreted by the kidney (CLR >300 mL/min) may be reduced from impairment in one or more of these renal transporters. Despite the different mechanisms involved in the elimination of drugs by the kidney and the availability of several methods for determining kidney function, the clinical estimation of CLCr remains the most commonly used index for guiding drug dosage regimen design. The importance of an alteration in kidney function on drug elimination usually depends on two variables: (1) the fraction of drug normally eliminated by the kidney unchanged and (2) the degree of kidney functional impairment. There are a few drugs for which a metabolite is the primary active entity; in that situation, a key variable is the degree of renal clearance of the metabolite. The calculation of CLCr from a timed urine collection has been the standard clinical measure of kidney function for decades. However, urine is difcult to collect accurately in most clinical settings, and the interference of many commonly used medications with creatinine measurement limits the utility of this approach. Use of radioactive markers ([125I]iothalamate, 51Cr-EDTA, or 99mTc-DTPA) or nonradioactive markers (iohexol, iothalamate, and inulin) of GFR, although scientically sound, is clinically impractical, because intravenous or subcutaneous marker administration and multiple timed blood and urine collections make the procedures expensive and cumbersome.

ESTIMATION OF KIDNEY FUNCTION FOR DRUG DOSING PURPOSES

The estimation of kidney function by various estimating equations for drug dosing purposes is a critically important issue. In contrast to measured approaches, estimation of CLCr or GFR requires only routinely collected laboratory and demographic data. The Cockcroft-Gault equation for CLCr and the equations for estimated GFR (eGFR) from the Modication of Diet in Renal Disease Study (MDRD) and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) correlate well with CLCr and GFR measurements in individuals with stable kidney function and average body composition (see Chapter 3). The traditional approach of estimating CLCr and using it as a continuous variable of kidney function for drug dosing adjustment purposes is now being supplementedand, in some institutions, replaced by eGFR. Caution is warranted because the use of eGFR as a guide for drug dosage adjustment has not been systematically validated. Currently, prospective pharmacokinetic data

Modied from Nolin TD, Unruh ML: Clinical relevance of impaired nonrenal drug clearance in ESRD, Semin Dial 23:482-485, 2010. CYP, Cytochrome P450 isozyme; MRP, multidrug resistanceassociated protein; NAT, N-acetyltransferase; OATP, organic anion-transporting polypeptide; P-gp, P-glycoprotein; UGT, uridine diphosphate-glucuronosyltransferases.

RENAL EXCRETION OF DRUGS

Renal clearance (CLR) is the net result of glomerular ltration of unbound drug plus tubular secretion minus tubular reabsorption. An acute or chronic reduction in GFR results in a decrease in CLR. The degree of change in total body clearance of a drug is dependent on the fraction of the dose

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and corresponding dosing recommendations based on GFR estimating equations are limited. Since nearly all of the primary published literature to date has used CLCr to derive the relationship between kidney function and renal and/ or total body clearance of a drug, CLCr is still the standard metric for drug dosing purposes. Nevertheless, widespread availability of automatically reported eGFR affords clinicians a tool that, if validated for drug dosing, could easily be incorporated into clinical practice. Furthermore, use of eGFR for management of kidney disease and drug dosing, along with harmonization of practice in this regard among physicians, pharmacists, and other clinicians, would be ideal and warrants further evaluation. Clinicians should consider several issues when assessing CLCr and eGFR data for drug dosing. First, the MDRD-derived eGFR is currently the most widely reported and provides an estimate that is normalized for body surface area (BSA) in units of mL/min/1.73 m2. When used for drug dosing, the eGFR value should be individualized, that is, not normalized for BSA, and converted to units of mL/min, particularly in patients whose BSA is considerably larger or smaller than 1.73 m2. The individualized value should be compared with CLCr estimates (mL/min). Second, when presented with various kidney function estimates that potentially translate into different drug dosing regimens, clinicians should choose the regimen that optimizes the risk-benet ratio given the patientspecic clinical scenario. For drugs with a narrow therapeutic range, typically more conservative kidney function estimates and corresponding doses should be used, particularly if therapeutic drug monitoring is not readily available. Since CLCr estimates are more conservative and indicate the need for dose adjustment more often than eGFR, they may be preferred when dosing drugs with narrow therapeutic windows, especially in high-risk subgroups such as older adults. Use of eGFR and a more aggressive dosing strategy may be acceptable for drugs with a wide therapeutic range and a broader margin of safety. Third, when estimating equations are not expected to provide accurate measures of kidney function (i.e., due to altered creatinine generation or unstable serum creatinine concentrations) and therapeutic drug monitoring is not available, it may be reasonable to obtain an accurately timed urine collection to calculate creatinine clearance, particularly for narrow-therapeutic-window drugs with high toxicity. Fourth, before applying data to a specic patient, clinicians must consider the limitations and the study population of the original trials from which the eGFR equations were developed, as well as the subsequent populations in which they have been validated. All of these methods are extremely poor predictors of kidney function in individuals with liver disease, and their use is not recommended for such patients. Finally, although several methods for CLCr estimation in patients with unstable kidney function (e.g., AKI) have been proposed, the accuracy of these methods has not been rigorously assessed, and at the present time their use cannot be recommended.

pharmacokinetic parameters of the drug and kidney function. Before 1998, there was no consensus regarding the criteria for characterizing the pharmacokinetics of a drug in patients with CKD. An industry report issued by the U.S. Food and Drug Administration in May 1998 provided guidelines regarding when a study should be considered; provided recommendations for study design, data analysis, and assessment of the impact of the study results on drug dosing; and recommended use of renal dose adjustment categories derived from CLCr . Currently, the FDA is considering including dosing tables based on eGFR and CLCr in a revised version of the 1998 FDA guideline. In the future, drug dosing recommendations based on eGFR in addition to CLCr , may be included in FDA-approved drug dosing labels. However, for drugs already approved by the FDA with existing renal dose adjustment recommendations based on CLCr , it is unlikely drug manufacturers will provide additional eGFR-based dosing recommendations. Most dosage adjustment references have proposed the use of a xed dose or interval for patients with a broad range of kidney function. Indeed, normal kidney function has often been ascribed to anyone who has a CLCr greater than 50 mL/ min, even though many individuals (e.g., hyperltering early diabetics) have values in the range of 120 to 180 mL/min. The moderate kidney function impairment category in many guides encompasses a vefold range of CLCr , from 10 to 49 mL/min, whereas severe kidney function impairment or ESRD is dened as a CLCr of less than 10 to 15 mL/min. Each of these categories encompasses a broad range of kidney function, and the calculated drug regimen may not be optimal for all patients within that range. If specic recommendations or data on the relationship of the pharmacokinetic parameters of a drug to CLCr are not available, then these parameters can be estimated for a particular patient using the method of Rowland and Tozer, provided that the fraction of drug that is eliminated unchanged by the kidney (fe) in normal subjects is known. This approach assumes the following: the change in drug clearance is proportional to the change in CLCr , kidney disease does not alter the drugs metabolism, any metabolites produced are inactive and nontoxic, the drug obeys rst-order (linear) kinetic principles, and it is adequately described by a one-compartment model. If these assumptions are true, the kinetic parameter or dosage adjustment factor (Q) can be calculated as follows:
Q = 1 [fe (1 KF)]

where KF is the ratio of the patients CLCr to the assumed normal value of 120 mL/min. As an example, the Q factor for a patient who has a CLCr of 10 mL/min and a drug that is 85% eliminated unchanged by the kidney would be:
Q = 1 [0.85(1 10/120) ] Q = 1 [0.85(0.92)] Q = 1 0.78 Q = 0.22

STRATEGIES FOR DRUG THERAPY INDIVIDUALIZATION

The design of the optimal dosage regimen for a patient with reduced kidney function depends on the availability of an accurate characterization of the relationship between the

The estimated clearance rate of the drug in this patient (CLPT) would then be calculated as
CLPT = CLnorm Q

where CLnorm is the respective value in patients with normal kidney function derived from the literature.

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For antihypertensive agents, cephalosporins, and many other drugs for which there are no target values for peak or trough concentrations, attainment of an average steadystate concentration similar to that in normal subjects is appropriate. The principal means to achieve this goal is to decrease the dose or prolong the dosing interval. If the dose is reduced and the dosing interval is unchanged, the desired average steady-state concentration will be near normal; however, the peak will be lower and the trough higher. Alternatively, if the dosing interval is increased and the dose remains unchanged, the peak, trough, and average concentrations will be similar to those in the patients with normal kidney function. This interval adjustment method is often preferred, because it is likely to yield signicant cost savings as the result of less frequent drug administration. If a loading dose is not administered, it will take 4 to 5 half-lives for the desired steady-state plasma concentrations to be achieved in any patient; this may require days rather than hours because of the prolonged half-life of many drugs in patients with reduced kidney function (RKF). Therefore to achieve the desired concentration rapidly, a loading dose (DL) should be administered for most patients with reduced kidney function. DL can be calculated as follows:
DL = (Cpeak) (VD) (Body weight in kilograms)

inuence drug clearance during CRRT are the ultraltration rate (UFR), the blood ow rate (BFR), and the dialysate ow rate (DFR), as well as the type of hemolter used. For example, clearance during CVVH is directly proportional to the UFR as a result of convective transport of drug molecules. Drug clearance in this situation is a function of the membrane permeability of the drug, which is called the sieving coefcient (SC), and the UFR. The SC can be approximated by the fraction of drug that is unbound to plasma proteins (fu), so the clearance can be calculated as follows:
CLCVVH = UFR SC

or

CLCVVH = UFR fu

Clearance during CVVHD also depends on the DFR and the SC of the drug. If UFR is negligible, CLCVVHD can be estimated to be maximally equal to the product of DFR and fu or SC. Clearance of a drug by CVVHDF is generally greater than by CVVHD, because drug is removed by diffusion as well as by convection/ultraltration. CLCVVHDF in many clinical settings can be mathematically approximated as:
CLCVVHDF = (UFR + DFR) SC

The loading dose is usually the same for patients with reduced kidney function as it is for those with normal kidney function. However, if the VD in patients with reduced kidney function is signicantly different from that VD in patients with normal kidney function (see Table 38.1), then the modied value should be used to calculate the DL. The adjusted dosing interval (RKF) or maintenance dose (DRKF) for the patient can then be calculated from the normal dosing interval (n) and normal dose (Dn), respectively:
RKF = n/Q DRKF = Dn Q

If these approaches yield a time interval or a dose that is impractical, a new dose can be calculated using a xed, prespecied dose interval (FPDI) such as 24 or 48 hours, as follows:
DRKF = [Dn Q FPDI ]/n

provided that the DFR is less than 33 mL/min and BFR is at least 75 mL/min. Changes in BFR typically have only a minor effect on drug clearance by any mode of CRRT, because BFR is usually much larger than the DFR and is therefore not the limiting factor for drug removal. Individualization of therapy for CRRT is based on the patients residual kidney function and the clearance of the drug by the mode of CRRT employed. The patients residual drug clearance can be predicted as described earlier in this chapter. CRRT clearance can also be approximated from published literature reports, although many of these reports did not specify all the operating conditions, and it may thus be hard to directly apply the ndings to a given patient situation. The clearances of several frequently used drugs by CVVH and CVVHDF are summarized in Table 38.3 and Table 38.4, respectively. Whenever feasible, plasma drug concentration monitoring for certain drugs such as aminoglycosides and vancomycin is highly recommended.

PATIENTS RECEIVING CHRONIC HEMODIALYSIS

Drug therapy in hemodialysis patients should be guided by careful evaluation of the patients residual kidney function, in addition to the added clearance associated with the patients dialysis prescription. Dosing recommendations are available for many agents, especially those with a wide therapeutic index. However, for those drugs with a narrow therapeutic index, individualization of the drug therapy regimen is highly recommended based on prospective serum concentration monitoring. Although many new hemodialyzers have been introduced in the past 15 years and the average delivered dose of hemodialysis has increased, the effect of hemodialysis on the disposition of a drug is rarely reevaluated after its initial introduction to the market. As a result, most of the published dosing guidelines underestimate the impact of hemodialysis on drug disposition, and clinicians should

PATIENTS RECEIVING CONTINUOUS RENAL REPLACEMENT THERAPY

Continuous renal replacement therapy is used primarily in patients with AKI. Drug therapy individualization for the patient receiving CRRT must take into account the fact that patients with AKI may have a higher residual CLNR of a drug than do CKD patients with similar level of kidney function. In addition to patient-specic differences, there are marked differences in the efciency of drug removal (see Chapter 58) among the three primary types of CRRT: continuous venovenous hemoltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodialtration (CVVHDF). The primary variables that

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Table 38.3 Drug Clearance and Dosing Recommendations for Patients Receiving Continuous Venovenous Hemoltration (CVVH)
Drug Acyclovir Amikacin Amrinone Atracurium Ceftazidime Ceftriaxone Cefuroxime Ciprooxacin Fluconazole Gentamicin Imipenem Levooxacin Meropenem Phenytoin Piperacillin Ticarcillin Tobramycin Vancomycin

Hemolter PS PS PS PA AN69, PMMA, PS AN69, PMMA, PS PA PS AN69 AN69 PS PS AN69 PA PS NR PS PS PA, PMMA,PS

CLT (mL/min, mean or range) 0.39 10.5 40.8 502.5 NR NR 39.3 32 84.4 25.3 11.6 108.3 42.3 76 NR 42 29.7 11.7 14-29

CLCVVH (mL/min, mean or range) NR 10-16 2.4-14.4 8.25 7.5-15.6 NR 17 11 12.4 17.5 3.47 13.3 11.5 16-50 1.02 NR 12.3 3.5 12-24

Dosage Recommendation 5 mg/kg q12h IND* None provided None provided 500 mg q12h 300 mg q12h 1000 mg q24h 0.75-1.0 g q24h 400 mg q24h 400-800 mg q24h IND* 500 mg q6-8h 250 mg q24h 0.5-1.0 g q12h IND* 4 g q12h 2 g q8-12h IND* 750-1250 mg q24h

Modied from Matzke GR, Clermont G: Clinical pharmacology and therapeutics. In Murray P, Brady HR, Hall JB, editors: Intensive Care Nephrology, London, Taylor and Francis, 2006. AN69, Acrylonitrile; CLCVVH, CVVH clearance; CLT, total body clearance; IND, individualize; NR, not reported; PA, polyamide lter; PMMA, polymethylmethacrylate lter; PS, polysulfone lter. *Serum concentrations may vary markedly depending on the patients condition; therefore dose individualization is recommended.

Table 38.4 Drug Clearance and Dosing Recommendations for Patients Receiving Continuous Venovenous Hemodialtration (CVVHDF)
Drug Acyclovir Ceftazidime Ceftriaxone Cefuroxime Ciprooxacin Fluconazole Ganciclovir Gentamicin Imipenem Levooxacin Meropenem Mezlocillin Sulbactam Piperacillin Teicoplanin Hemolter AN69 AN69, PMMA, PS AN69 PMMA, PS AN69 AN69 AN69 AN69 AN69 AN69, PS AN69 PAN AN69, PS AN69, PS AN69 AN69 CLT (mL/min, mean or range) 1.2 25-31 22 264 21-38 32 20 134 51 55-140 31-253 32-54 47 9.2 CLCVVHDF (mL/min, mean or range) NR 13-28 11.7-13.2 19.8-30.5 14-16.2 16-37 25-30 13 5.2 16-30 22 20-39 11-45 10-23 22 3.6 Dosage Recommendation 5 mg/kg q12h 0.5-1 g q24h 250 mg q12h 300 mg q12h 750 mg q12h 300 mg q12h 400-800 mg q12h 2.5 mg/kg q24h IND* 500 mg q6-8h 250 mg q24h 1000 mg q8-12h 2-4 g q24h 0.5 g q24h PIP: 4 g q12h PIP/TAZO: 3.375 g q8-12h LD: 800 mg MD: 400 mg q24h 2, then q48-72h 7.5 mg/kg q12h 1.0-1.5 g q24h 0.85-1.35 g q24h

Vancomycin

AN69 PMMA PS

17-39 36

10-17 15-27.0 11-22

Modied from Matzke GR, Clermont G: Clinical pharmacology and therapeutics. In Murray P, Brady HR, Hall JB, editors: Intensive Care Nephrology, London, Taylor and Francis, 2006. AN69, Acrylonitrile; CLCVVHD, CVVDH clearance; CLT, total body clearance; IND, individualize; LD, loading dose; MD, maintenance dose; NR, not reported; PA, polyamide lter; PAN, polyacrylonitrile lter; PMMA, polymethylmethacrylate lter; PS, polysulfone lter; TAZO, tazobactam. *Serum concentrations may vary markedly depending on the patients condition; therefore dose individualization is recommended.

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Table 38.5 Drug Disposition during Dialysis Depends on Dialyzer Characteristics

Hemodialysis Clearance (mL/min) Drug Ceftazidime Cefuroxime Foscarnet Gentamicin Tobramycin Ranitidine Vancomycin Conventional 55-60 NR 183 58.2 45 43.1 9-21 High-Flux 155 (PA) 103 (PS) 253 (PS) 116 (PS) 119 (PS) 67.2 (PS) 31-60 (PAN) 40-150 (PS) 72-116 (PMMA) Half-Life During Dialysis (hr) Conventional 3.3 3.8 NR 3.0 4.0 5.1 35-38 High-Flux 1.2 (PA) 1.6 (PS) NR 4.3 (PS) NR 2.9 (PS) 12.0 (PAN) 4.5-11.8 (PS) NR

NR, Not reported; PA, polyamide lter; PAN, polyacrylonitrile lter; PMMA, polymethylmethacrylate; PS, polysulfone lter.

cautiously consider the prescription of doses that are larger than those conventionally recommended for their critically ill patients. The effect of hemodialysis on a patients drug therapy depends on the molecular weight, protein binding, and distribution volume of the drug; the composition of the dialyzer membrane and its surface area; BFR and DFR; and whether the dialyzer is reused. Drugs that are small molecules but highly protein-bound are not well dialyzed because the two principal binding proteins (1-acid glycoprotein and albumin) are high-molecular-weight entities. Finally, drugs with a large volume of distribution are poorly removed by hemodialysis. Conventional or low-ux dialyzers are relatively impermeable to drugs with a molecular weight greater than 1000 daltons (Da). High-ux hemodialyzers allow the passage of most drugs that have a molecular weight of 10,000 Da or less. The determination of drug concentrations at the start and end of dialysis, with subsequent calculation of the halflife during dialysis, has historically been used as an index of drug removal by dialysis. A more accurate means of assessing the effect of hemodialysis is to calculate the dialyzer clearance rate (CLD) of the drug. Because drug concentrations are generally measured in plasma, the plasma clearance of the drug by hemodialysis (CLpD) can be calculated as follows:
CLpD = Q p([A p Vp]/A p)

where (VD C) is the amount of drug in the body at the start of dialysis, e-kt is the fraction of drug remaining as a result of the patients residual total body clearance during the dialysis procedure, and e-kHDt is the fraction of drug remaining as a result of elimination by the dialyzer:
kHD = CLpD /VD

where Ap is arterial plasma concentration, Vp is venous plasma concentration, and Qp is the plasma ow rate calculated as:
Qp = BFR (1 Hematocrit)

Recently, alternative dosing strategies were evaluated for some drugs, such as gentamicin and vancomycin, in which the drug was administered before or during the dialysis procedure. These approaches may save time in the ambulatory dialysis setting but will increase drug cost because more drug will have to be given to compensate for the increased dialysis removal. Values for CLpD of some commonly used drugs are listed in Table 38.5. This information serves only as initial dosing guidance; measurement of predialysis serum concentrations is recommended to guide subsequent drug dosing. The impact of hemodialysis on drug therapy must not be viewed as a generic procedure that will result in removal of a xed percentage of the drug from the body with each dialysis session; neither should simple yes/no answers on the dialyzability of drug compounds be considered sufcient information for therapeutic decisions. Compounds considered nondialyzable with low-ux dialyzers may in fact be signicantly removed by high-ux hemodialyzers.

PATIENTS RECEIVING CHRONIC PERITONEAL DIALYSIS

Peritoneal dialysis has the potential to affect drug disposition, but drug therapy individualization is often less complicated in these patients because of the relative inefciency of the procedure per unit time. Variables that inuence drug removal in peritoneal dialysis include drugspecic characteristics such as molecular weight, solubility, degree of ionization, protein binding, and volume of distribution. Patient-specic factors include peritoneal membrane characteristics such as splanchnic blood ow, surface area, and permeability. The contribution of peritoneal dialysis to total body clearance is often low and, for most drugs, markedly less than the contribution of

This clearance calculation accurately reects dialysis drug clearance only if drug does not penetrate or bind to formed blood elements. For patients receiving hemodialysis, the usual objective is to restore the amount of drug in the body at the end of dialysis to the value that would have been present if the patient had not been dialyzed. The supplementary dose (DpostHD) is calculated as follows:
DpostHD = [VD C](e-k t e-kHD t )

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SECTION 6 DRUGS AND THE KIDNEY

hemodialysis per unit time. Antiinfective agents are the most commonly studied drugs because of their primary role in the treatment of peritonitis, and the dosing recommendations for peritonitis, which are regularly updated, should be consulted as necessary. Most other drugs can generally be dosed according to the residual kidney function of the patient because clearance by peritoneal dialysis is small. If there is a signicant relationship between the desired peak (Cpeak) or trough (Ctrough) concentration of a drug for a given patient with reduced kidney function and the potential clinical response (e.g., aminoglycosides) or toxicity (e.g., quinidine, phenobarbital, phenytoin), then attainment of the target plasma concentration value is critical. In these situations, the adjusted dosage interval (RKF) and maintenance dose (DRKF) for the patient can be calculated as follows:
RKF = ([1/kPT] ln[Cpeak/Ctrough]) + tinf DRKF =[kPT VD Cpeak ] [1 e-(kPT)(RKF)/1 e-(kPT)(tinf)]

Box 38.1  Key Recommendations for

Clinicians

1.  Over-the-counter and herbal products, as well as prescription medications, should be assessed to ensure that they are indicated. 2.  The least nephrotoxic agent should be used whenever possible. 3.  If a drug interaction is suspected and the clinical implication is signicant, alternative medications should be used. 4.  Although the MDRD eGFR equation may be used for staging CKD, the Cockcroft-Gault equation remains the standard kidney function index for drug dosage adjustment. 5.  The dosage of drugs that are more than 30% renally eliminated unchanged should be veried to ensure that appropriate initial dosage adjustments are implemented. 6.  Maintenance dosage regimens should be adjusted based on patient response and serum drug concentration determinations when indicated and available. CKD, Chronic kidney disease; eGFR, estimated glomerular ltration rate; MDRD, Modication of Diet in Renal Disease.

where tinf is the infusion duration, kPT is the elimination rate constant of the drug for that patient, which can be estimated as: kPT = knorm Q and VD is the volume of distribution of the drug that can be obtained from literature values such as those in Table 38.1. This estimation method assumes that the drug is administered by intermittent intravenous infusion and its disposition is adequately characterized by a one-compartment linear model.

CONCLUSIONS
The adverse outcomes associated with inappropriate drug use and dosing are largely preventable if the principles illustrated in this chapter are used by the clinician in concert with reliable population pharmacokinetic estimates to design rational initial drug dosage regimens for patients with reduced kidney function and those needing dialysis. Subsequent individualization of therapy should be undertaken whenever clinical therapeutic monitoring tools, such as plasma drug concentrations, are available. These key recommendations for practice are highlighted in Box 38.1. BIBLIOGRAPHY
Aronoff GR, Bennetl WM, Berns JS, etal: Drug prescribing in renal failure: dosing guidelines for adults and children, ed 5, Philadelphia, 2007, American College of Physicians-American Society of Internal Medicine. Heintz BH, Matzke GR, Dager WE: Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis, Pharmacotherapy 29:562-577, 2009. Lee W, Kim RB: Transporters and renal drug elimination, Annu Rev Pharmacol Toxicol 44:137-166, 2004. Matzke GR: Status of hemodialysis of drugs in 2002, J Pharm Practice 15:405-418, 2002. Matzke GR, Aronoff GR, Atkinson AJ Jr, etal: Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO), Kidney Int 80:1122-1137, 2011. Matzke GR, Clermont G: Clinical pharmacology and therapeutics. In Murray PT, Brady HR, Hall JB, editors: Intensive care in nephrology, Boca Raton, Fla, 2006, Taylor and Francis, pp 245-265. Matzke GR, Comstock TJ: Inuence of renal disease and dialysis on pharmacokinetics. In Evans WE, Schentag JJ, Burton ME, editors: Applied pharmacokinetics: principles of therapeutic drug monitoring, ed 4, Baltimore, 2005, Lippincott Williams and Wilkins. Mueller BA, Pasko DA, Sowinski KM: Higher renal replacement therapy dose delivery inuences on drug therapy, Artif Organs 27:808-814, 2003.

CLINICAL DECISION SUPPORT TOOLS

The availability of health information technologynamely, clinical decision support toolshas increased substantially in recent years, and use of these tools may facilitate renal drug dosing by providing consistent, accurate dosing recommendations in real time. Clinical decision support systems (CDSS) are commonplace in institutional health information computer systems, and their incorporation into computerized provider order entry (CPOE) systems has been shown to improve medication use in CKD and AKI patient populations. In addition, CDSS make individual assessments and comparisons of kidney function estimates feasible. For example, CDSS can easily accommodate new equations (e.g., CKD-EPI) as they become available and facilitate conversion of the MDRD Study equationderived eGFR to individualized values by modifying units of mL/min/1.73 m2 to units of mL/min. Numerous other resources are available for renal drug dosing information, including online sources, as well as portable handheld databases such as Epocrates, Lexicomp, and Micromedex. The American Hospital Formulary Service Drug Information text, the British National Formulary, Aronoffs Drug Prescribing in Renal Failure, and Martindale's Complete Drug Reference are excellent resources for drug dosage recommendations for patients with impaired kidney function. All of these are accessible electronically and/or online.

CHAPTER 38 PRINCIPLES OF DRUG THERAPY IN PATIENTS WITH REDUCED KIDNEY FUNCTION Munar MY, Singh H: Drug dosing adjustments in patients with chronic kidney disease, Am Fam Physician 75:1487-1496, 2007. Naud J, Nolin TD, Leblond FA, etal: Current understanding of drug disposition in kidney disease, J Clin Pharmacol 52:10S-22S, 2012. Nolin TD, Frye RF, Le P, etal: ESRD impairs nonrenal clearance of fexofenadine but not midazolam, J Am Soc Nephrol 20:2269-2276, 2009. Nolin TD, Naud J, Leblond FA, etal: Emerging evidence of the impact of kidney disease on drug metabolism and transport, Clin Pharmacol Ther 83:898-903, 2008. Nyman HA, Dowling TC, Hudson JQ, etal: Comparative evaluation of the Cockcroft-Gault Equation and the Modication of Diet in Renal Disease (MDRD) study equation for drug dosing: an opinion of the Nephrology Practice and Research Network of the American College of Clinical Pharmacy, Pharmacotherapy 31:1130-1144, 2011.

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Piraino B, Bailie GR, Bernardini J, etal: Peritoneal dialysis related infections: 2005 Update, Perit Dial Int 25:107-131, 2005. van dijik EA, Drabbe NRG, Kruijtbosch M, etal: Drug dosage adjustments according to renal function at hospital discharge, Ann Pharmacother 40:1254-1260, 2006. Veltri MA, Neu AM, Fivush BA, etal: Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special considerations in pediatric patients, Pediatr Drugs 6:45-65, 2004. Verbeeck RK, Musuamba FT: Pharmacokinetics and dosage adjustment in patients with renal dysfunction, Eur J Clin Pharmacol 65:757-773, 2009. Vidal L, Shavit M, Fraser A, etal: Systematic comparison of four sources of drug information regarding adjustment of dose for renal function, BMJ 331:263-266, 2005.