The World Health Organization estimates

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1 Estimating the Glomerular Filtration Rate in Obese Adult Patients for Drug Dosing Manjunath P. Pai One-third of adult Americans are currently classified as obese. Physiologic changes associated with obesity can potentially alter the clearance of commonly used drugs. Clearance of certain drugs by the kidneys occurs primarily through glomerular filtration and tubular secretion. Obesity has been associated with glomerular hyperfiltration, whereas obesity-related effects on tubular secretion are not well characterized. Estimation of the glomerular filtration rate (GFR) is currently performed using serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. However, drug dosing guidelines are often based on creatinine clearance (CLcr) using the Cockcroft-Gault equation as a surrogate of GFR. There is a lack of consensus on the most appropriate method for estimation of GFR or CLcr in patients with obesity. The controversy relates to the use of 2 body size descriptors that confound these equations. The Cockcroft-Gault equation relies on total body weight and so overestimates GFR in patients with obesity. The MDRD equation indexes GFR based on a normalized body surface area, that is, ml/min/1.73 m 2. Conversion of MDRD estimated GFR to non-normalized body surface area overestimates GFR in patients with obesity. The current review explores current approaches and controversies to estimation of GFR and CLcr among obese patients in clinical practice. The role of the alternate body size descriptor, lean body weight to estimate CLcr in obese patients is reviewed. Q 2010 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Chronic kidney disease, Creatinine clearance, Glomerular filtration rate, Obesity, Pharmacokinetics The World Health Organization estimates that 400 million persons are currently obese and project that 700 million persons will be obese by the year One third of the U.S. adult population is now classified as obese, which is defined as a body mass index (BMI) $30 kg/m 2. 2 Although the prevalence of obesity has increased over the past five decades, studies that evaluate the disposition of drugs continue to evaluate normal weight individuals. 3 Use of a referent kg individual with a body surface area (BSA) of 1.73 m 2 is no longer representative of a normal average adult in the United States. The U.S. adult population has on average gained slightly less than an inch in height and 25 pounds in weight over the past 50 years. 4 Hence, the mean height/weight for males and females in the United States in was 1.76 m/ 86.8 kg and 1.62 m/74.7 kg, respectively. 4 Consequently, the average estimated BSA using Mosteller s equation is now 2.06 m 2 and 1.83 m 2 for males and females, respectively, in the United States. 4,5 Obesity predisposes individuals to cardiovascular complications, diabetes mellitus, and some cancers. 6 Obesity independently and in concert with these complications can also predispose individuals to develop chronic kidney disease (CKD). 7 Higher BMIs have been shown in recent epidemiologic studies to be contributing to an increased prevalence of CKD over the past two decades. 8 Understanding the interrelationship of obesity on kidney function is critical given that several drugs and drug metabolites are eliminated through the kidney. Drug and drug metabolite elimination through the kidney occurs through glomerular filtration, tubular secretion, and tubular reabsorption. 9 Clinically, drug dose adjustment has been based solely on estimation of drug clearance through surrogate measures of glomerular filtration. 10 The influence of obesity on renal tubular secretion and renal tubular reabsorption is not well known and no objective clinical measure of these drug clearance pathways presently exists. 3 As a result, alteration of drug doses and dosing intervals in product labels are often based on estimates of the From Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY. Address correspondence to Manjunath P. Pai, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, O Brien Room 204, Albany, NY amit. pai@acphs.edu Ó 2010 by the National Kidney Foundation, Inc. All rights reserved /$36.00 doi: /j.ackd Advances in Chronic Kidney Disease, Vol 17, No 5 (September), 2010: pp e53-e62 e53

2 e54 Pai glomerular filtration rate (GFR) measured clinically using the surrogate estimate, creatinine clearance (CLcr). 11 Estimates of CLcr are often incorporated into population pharmacokinetic models to define doses in broader populations than those studied in the clinical trials. 12,13 This is important given that the data used to derive population pharmacokinetic models often include phase 1 and 2 studies, which primarily include normal weight subjects. 14 Despite this exclusion, drugs are ultimately used in a heavier population than are studied in controlled trials. 2,14 Reevaluation of the disposition of all marketed drugs to define the most appropriate dose in obese subjects is unlikely to occur. Hence, identification of the most appropriate method of scaling doses across BMI categories is critical. 15 Anecdotal evidence suggests that clinicians may adjust doses on the basis of total body weight (TBW). 16 This approach assumes that drug clearance increases in proportion to TBW. However, drug clearance through the kidney is not proportional to TBW Furthermore, estimation of drug dosing intervals (for drugs removed by the kidney) has been based on CLcr estimated using Cockcroft-Gault (CG) equation. 11,20 The CG equation estimates CLcr using TBW, and thus overestimates CLcr in obese patients. 21 In the past decade, the modification of diet in renal disease (MDRD) and chronic kidney disease and epidemiology (CKD-EPI) equations have emerged as contenders to replace the use of the CG equation. 22,23 The MDRD and CKD- EPI equations do not include TBW as a parameter but instead index GFR to BSA. 22,23 Current equations overestimate GFR in obese patients when the GFR is transformed by the estimated BSA. This article explores current methods and controversies to estimation of GFR and CLcr among obese patients in clinical practice. The intrinsic flaws and potential solutions to estimation of GFR and CLcr are highlighted when using current equations. Relationship of Body Size to Kidney Function Body size is measured in the clinic as height and weight and used to estimate the common body size descriptors, BMI and BSA. The origin and role of BSA to index GFR has been reviewed with specific emphasis on the difficulty of measuring BSA among obese subjects. 24 Data from human subjects weighing 51.3 to kg has been used to show that BSA scales to weight geometrically, where BSA ¼ C 3 Weight b, where C represents a constant and b represents an exponent. 25 The exponent to scale body weight to BSA is consistent with geometric scaling such that all surface area-based properties change with mass to the 2/3 power (b ¼ 0.67). The GFR of mammals is closely related to the basal metabolic rate (BMR). 26 The interrelationship of BMR to body size across species is generally governed by the quarter-power law, where BMR ¼ C 3 Weight b. 27 However, the universality of the exponent b remains unresolved (over a century) with the central arguments competing between quarter-power scaling (b ¼ 0.75) or geometric scaling (b ¼ 0.67). 27 Review across species of the clearance of 21 xenobiotics that are eliminated by renal excretion reveals that the mean (95% Confidence Interval) exponent b was 0.65 ( ), when comparing clearance with weight. 28 Hence, the scaling of GFR to BSA although not initially driven by strong scientific rationale is not entirely unreasonable when considering drug dosing. 24 Nonetheless, alternate scalars such as extracellular fluid volume and lean body weight are equally relevant when considering GFR and drug dosing in obese subjects. 14,17,18,21,29,30 Despite the controversies of body size indexation, a perfect relationship of body size to kidney function is unlikely to be resolved in the near term. Weight and height remain practical and measurable body size parameters in the clinic. As such, an understanding of the association of these covariates to kidney function is critical. 31 The relationship of TBW to organ weight and function is used in the science of physiologically based pharmacokinetic (PBPK) modeling. 31 Modeling using PBPK methods use estimates of blood flow rates and organ weight to predict the distribution and clearance of drugs. However, PBPK models have been limited by organ weight data from the International Consortium for Radiological protection 1975 document with

3 Estimating GFR for Drug Dosing in Obesity e55 an upper weight limit of 65 kg for females and 75 kg for males. 32 Given this limitation, Young and colleagues developed human organ/tissue growth algorithms using autopsy data that included obese black and white racial populations. 32 The goal of this work was to permit organ/tissue weight projections in individuals 50 to 250 kg in weight. 32 An illustration of the fractional change in male kidney, liver, and heart size as a function of TBW between 50 and 250 kg is illustrated in Figure As demonstrated, the change in organ size relative to body size is nonlinear. These data reveal that a doubling in TBW equates to a mean 64% increment in the size of an individual s kidneys, and that the size of the kidney does not continue to increase in proportion to TBW. The changes in kidney size relative to weight are concordant with data evaluating GFR in obese (normotensive, nondiabetic) subjects compared with normal weight subjects. 33 Chagnac and colleagues measured GFR using an inulin based method in 12 obese (BMI. 36 kg/m 2 ) compared with 19 age and gender matched healthy normal weight (BMI # 25 kg/m 2 ) subjects. 33 The mean 6 SD GFR in obese subjects and normal weight subjects was ml/min and ml/min, respectively. 33 The mean 6 SD TBW in the obese and normal weight subjects was kg and kg, respectively. As demonstrated, the obese group had twice the mean TBW than the normal weight group but only a 62% higher mean GFR. These data clearly reveal that kidney size and GFR is not proportional to TBW requiring the evaluation of alternate body size descriptors (ABSD). 18,24,29,30,33 ABSD to Estimate GFR Body size and composition can be measured through techniques such as bioelectric impedance analysis, underwater weighing, dualenergy x-ray absorptimetry, anthropometry, magnetic resonance imaging, and air displacement plethysmography. 3,17 As expected, these techniques are not simple to apply in the acute clinical setting and so require approaches that estimate body size. Several ABSD have been developed over the past century. 17 The ABSD include ideal body weight (IBW), adjusted body weight, lean body weight published in 1976 (LBW 1976 ), fat free weight, predicted normal weight (PNWT), and lean body weight published in 2005 (LBW 2005 ). 17,34 In addition, several very comparable BSA functions have been developed by DuBois and DuBois (BSA_DD), Gehan and George (BSA_GG), Haycock and colleagues (BSA_H), Mosteller (BSA_M), and Livingstone and Lee (BSA_LL). 5,17,24,25 Although, the motivation for generation of ABSD has not been drug dosing, these descriptors have been used successfully to estimate drug dosing. 17 Asummary of some commonly used ABSD and functions used to calculate them are listed in Table 1. Inclusion of every ABSD developed to date was considered to be beyond the scope of this review. In general, the ABSD functions of weight include three key covariates namely height, weight, and gender formulated as linear or nonlinear functions. The exception to this is IBW, which is estimated based on height and gender alone. 35 The key difference between ABSD of weight versus BSA is that functions of BSA do not adjust for potential body size differences between the genders. 17 Finally, the only BSA function to have included subjects over 200 kg has been BSA_LL, which only relies on weight to estimate BSA. 25 As expected, the presented 11 examples of ABSD pose enormous confusion to clinicians when selecting a dose and dose interval. Current knowledge supports the idea that selection of an ABSD is drug dependent. 17 However, a key difference exists between the ABSD that supports the promotion of LBW 2005 as the best contemporary ABSD of weight. Figure 2 illustrates the fractional change in ABSD of weight versus TBW when using a 50 kg male subject with a height of 176 cm (5 9") as the reference. As illustrated, IBW is not affected by TBW, whereas adjusted body weight and fat free weight increase linearly with TBW. In contrast, LBW 1976, PNWT, and LBW 2005 increase nonlinearly with TBW. However, parameterization of LBW 1976 and PNWT with negative functional components results in a decline in the estimated body size above a TBW of 125 kg. Hence in this example, LBW 1976 and PNWT are not useful ABSD in obese subjects with a TBW above

4 e56 Pai Figure 1. The fractional change in tissue/organ weight as a function of total body weight in male subjects between 50 kg and 250 kg, using data from a 50-kg subject as the reference. 32 approximately 125 kg or a BMI above approximately 50 kg/m 2. LBW 2005 demonstrates a fractional change in size that mimics the expected change in kidney size between 50 and 125 kg and very similar to the change in liver and heart size across the range of 50 to 250 kg. Figure 3 illustrates the fractional change in ABSD of BSA relative to TBW using the aforementioned reference subject and inclusion of LBW As illustrated, LBW 2005 scales to TBW in a very similar fashion to equations used to estimate BSA, with the exception of BSA_DD and BSA_LL. Most striking is the comparable scaling of LBW 2005 and BSA_M to TBW with deviation between these ABSD noted at a TBW above approximately 200 kg. Although the illustrated example is that of a male subject, a comparable relationship is noted between LBW 2005 and BSA_M when evaluating females. These assessments of ABSD are critical given the need for selection and use of a singular ABSD for drug dosing against a clinical background of increasing obesity and complex pharmacologic management. As previously mentioned, the most appropriate ABSD is likely drug dependent. However, when estimating kidney function across TBW, use of LBW 2005 and BSA_M are very comparable and easy to estimate scalars. Simply put, LBW 2005 provides the necessary curvature in the weight parameter when considering extremes of weight as in the case of obesity. Estimating GFR for Drug Dosing in Obesity Adjustment of drug dosing for drugs eliminated through the kidney has been based on the CG equation. 11,20 Population pharmacokinetic models used to define drug dosing are likely to continue to use the CG equation Product labels for drugs that require dose adjustment in patients with reduced GFR have used the CG equation though use of the MDRD is likely to be recommended by the U.S. Food and Drug Administration. 36 The pros and cons of the CG and MDRD equation to define drug dosing have recently been debated. 37,38 The CG equation estimates CLcr as a surrogate of GFR. Clearance of the endogenous substrate creatinine in serum (Scr) is dependent on GFR and renal tubular secretion. 37 The endogenous production of creatinine is reliant on diet and muscle mass. Muscle mass is

5 Estimating GFR for Drug Dosing in Obesity e57 Table 1. Common Alternate Body Size Descriptors Used to Define the Body Size of Obese Subjects 17,25,34 Body Size Descriptor Equation Total body weight (TBW), kg Measured Ideal body weight (IBW), kg Males ¼ (Ht per inch over 5 ft) Females ¼ (Ht per inch over 5 ft) Adjusted body weight (ABW), kg IBW (TBW 2 IBW) Lean body weight 1976 (LBW 1976 ), kg Males ¼ TBW BMI 3 TBW Females ¼ TBW BMI 3 TBW Fat free weight (FFW), kg Males ¼ TBW (Ht in m) 2 Females ¼ TBW (Ht in m) 2 Predicted normal weight (PNWT), kg Males ¼ TBW BMI 3 TBW Females ¼ TBW BMI 3 TBW Lean body weight 2005 (LBW 2005 ), kg Males ¼ ( TBW)/( BMI) Females ¼ ( TBW)/( BMI) Body surface area (BSA), m 2 TBW (kg), Ht (cm) DuBois and DuBois (BSA_DD) TBW Ht Gehan and George (BSA_GG) TBW Ht Haycock and colleagues (BSA_H) TBW Ht Mosteller (BSA_M) [(TBW 3 Ht)/3600] 0.5 Livingstone and Lee (BSA_LL) TBW dependent on age, gender, TBW, and presence or absence of comorbidities. 37 The use of Scr to estimate CLcr and GFR has several limitations that cannot be resolved easily without use of an alternate endogenous substrate. 37,38 The most viable alternate substrate known as cystatin C is not yet readily available and has the potential to misclassify obese subjects with CKD. 39,40 Hence, the use of Scr is likely to continue to be used to estimate GFR in the clinic for the foreseeable future Muscle mass does not increase proportionally to TBW but instead increases in proportion to LBW. Hence, Scr is expected to correlate to LBW and not TBW. 32 Consequently, the use of TBW in the CG equation is an intrinsically flawed approach. The MDRD was developed nearly two decades ago as a six variable function of age, gender, Scr, blood urea nitrogen, albumin, and race (black or not black) to estimate GFR in patients with Scr values above 1.4 mg/dl. 22 The MDRD equation was generated using a relatively large patient sample and use of the more reliable exogenous substrate, radiolabeled iothalamate to estimate GFR. The MDRD equation, which is now limited to 4 variables (age, gender, Scr, and race), has been advocated as the most reliable clinical estimator of GFR in patients with agfr,60 ml/min/1.73 m In addition, the MDRD equation has been modified to correct for Scr assays have been calibrated against an isotopic dilution mass spectrometry (IDMS) traceable method. 37 The National Kidney Foundation has promoted the use of the MDRD equation as a tool to stage CKD. An estimated 70% of institutions in the United States now automatically report individual patient GFR values when a Scr measurement is ordered. 41 Hence, clinicians can readily access GFR estimates without having to estimate CLcr using the CG equation. However, the appropriateness of using CLcr estimated using the CG equation versus GFR estimated using the MDRD equation as measures that are equivalent to drive drug dosing is contentious. 37,38 The National Kidney Disease Education Program released a document in September of 2009 to inform clinicians of this debate and provided four key recommendations. 42 These recommendations include: (1) use of a single equation within a healthcare institution to drive detection, evaluation, and management of CKD and drug dosing; (2) use estimated GFR (egfr, inferred to be the MDRD equation) or estimated CLcr (eclcr, inferred to be CG equation); (3) if using egfr in very large or very small patients, multiply the egfr by BSA to convert the units of egfr from ml/min/1.73 m 2 to ml/min, and provide the BSA_M equation as an example;

6 e58 Pai Figure 2. The fractional change in alternate body size (weight) descriptors as a function of total body weight in male subjects between 50 kg and 250 kg, using data from a 50-kg, 176-cm subject as the reference. 17,34 Abbreviations: IBW, ideal body weight; ABW, adjusted body weight; LBW 1976, lean body weight published in 1976; FFW, fat free weight; PNWT, fat free weight; LBW 2005, lean body weight published in and (4) consider measuring GFR or CLcr when using drugs with narrow therapeutic indices. The document provides the reader with an excellent summary of the pros and cons of each equation and approach to drug dosing. 42 However, this document fails to consider ABSD such as LBW 2005 when using the CG equation. As noted in previous sections, BSA normalizes GFR but is not the only viable scalar when treating obese patients. Several investigators have demonstrated that GFR normalized to LBW (measured or estimated) corrects for differences observed with absolute GFR measurements in obese subjects. 18,21,24,43 Ozmen and colleagues have recently demonstrated that CLcr is best predicted by the ratio of LBW/ Scr across all weight strata, that is, very small to very large. 43 Demirovic and colleagues measured CLcr in 54 individuals with a TBW of 99 to 320 kg. Use of LBW 2005 provided an unbiased estimate of CLcr when used as the weight parameter in CG equation. 21 As illustrated in Figure 4A and 4B, the MDRD equation corrected for BSA overestimates 24-hour measured CLcr when compared with the use of CG equation with LBW 2005 (CG_LBW) in obese individuals, respectively. 21 The limitations of the MDRD equation in individuals with egfr $60 ml/min/1.73 m 2 is well known and patients with GFR values above this limit are technically supposed to be reported as $60 ml/min/1.73 m The CKD-EPI equation was developed to overcome this limitation. 23 Although the CKD-EPI equation provides unbiased estimates of GFR in patients with GFR $60 ml/min/1.73 m 2, it suffers the same limitation of BSA transformation for dose modification. 23 Table 2 provides point estimates of eclcr and egfr for a 50-year-old non-black adult using CG_LBW, MDRD, and the CKD-EPI equation as comparable units of ml/min. As demonstrated in this table, the MDRD and CKD-EPI equations leads to consistently higher point estimates of kidney function compared with CG_LBW, especially at the extremes of weight in patient unlikely to have CKD.

7 Estimating GFR for Drug Dosing in Obesity e59 Figure 3. The fractional change in alternate body size (body surface area and lean body weight) descriptors as a function of total body weight in subjects between 50 kg and 250 kg, using data from a 50-kg, 176-cm male subject as the reference. 17,25 Abbreviations: BSA_DD, Body surface area using the DuBois and DuBois equation; BSA_GG, BSA using the Gehan and George equation; BSA_H, BSA using the Haycock and colleagues equation; (BSA_M)BSA using the Mosteller equation; BSA_LL, BSA using the Livingstone and Lee; LBW 2005, lean body weight published in Practical Considerations Rational dose selection requires an appreciation of dose-exposure relationships across the intended clinical population. Hence, population pharmacokinetic modelers cannot be expected to use the MDRD equation to estimate GFR as a predictor of drug clearance given that this equation is restricted to individuals with a GFR,60 ml/min/1.73 m 2. The CKD- EPI equation will provide modelers an opportunity to design functions of drug clearance without the later limitation on GFR estimation. Thus, the likely transition in the coming decade away from the MDRD equation to say the CKD-EPI equation will again create discordance in drug labeling recommendations versus clinical laboratory results. Hence, modifications to regulatory guidance and drug labeling for dose adjustment should be undertaken thoughtfully. 36 Simply put, it is unreasonable to recommend that the pharmaceutical industry estimate GFR using the MDRD equation with knowledge that the CKD-EPI equation may be better. A recent study that evaluated 15 agents to validate the equivalence of using the MDRD versus CG equation is an excellent first step. 44 This later study used TBW and IBW as weight parameters in the CG equation, which although common clinical practice would be irrational in obese patients. 44 However, the role and integration of the CKD- EPI equation into the drug dosing paradigm remains to be defined and should be explored by population pharmacokinetic modelers. The CG equation in contrast is unlikely to change hence the only stepwise modification of the CG equation is use of LBW 2005 instead of TBW to estimate CLcr in obese subjects. Use of LBWestimated using LBW 2005 in the existing CG equation is the most practical approach to estimating CLcr in obese patients. In the case of obese patients, use of the CG equation and LBW 2005 is more useful than the use of MDRD with BSA_M to estimate CLcr. Clinicians must recognize that use of the MDRD or CG equation can result in drug dosing discordance. 45 The relative merits of

8 e60 Pai Figure 4. Residual versus estimated glomerular filtration rate or creatinine clearance when comparing the Modification of Diet in Renal Disease (isotopic dilution mass spectrometry traceable) equations transformed with BSA_M (A) and the CG_LBW (B) relative to measured 24-hour CLcr in morbidly obese subjects. 21

9 Estimating GFR for Drug Dosing in Obesity e61 Table 2. Point Estimates of Creatinine Clearance and Glomerular Filtration Rate Using Clinically Relevant Equations for A 50-Year-Old Nonblack Adult at Three Tiers of Weight and Serum Creatinine, With Height Held Constant 17 Parameter Male Female Weight (kg) Height (inches) BMI (kg/m 2 ) BSA_M (m 2 ) LBW 2005 (kg) CG_LBW (ml/min) Scr ¼ 0.7 mg/dl Scr ¼ 1.4 mg/dl Scr ¼ 2.1 mg/dl MDRD (ml/min) Scr ¼ 0.7 mg/dl Scr ¼ 1.4 mg/dl Scr ¼ 2.1 mg/dl CKD-EPI (ml/min) Scr ¼ 0.7 mg/dl Scr ¼ 1.4 mg/dl Scr ¼ 2.1 mg/dl Abbreviations: BMI, body mass index; BSA_M, body surface area using the Mosteller equation; LBW 2005, estimated lean body weight 34 ; CG_LBW, Cockcroft and Gault equation with LBW 2005 as the weight parameter; Scr, serum creatinine; MDRD, modification of diet in renal disease equation, 4-variable IDMS function; CKD-EPI, chronic kidney disease epidemiology equation. the CKD-EPI equation in obese subjects remains to be defined. Use of the CG equation with replacement of LBW 2005 for TBW to guide drug dosing is a practical approach when treating obese patients. Summary Clinicians are faced with an increasing population of obese patients who require dosing adjustment of drugs that are cleared by the kidney. Drug clearance is estimated using equations to approximate CLcr and GFR to aid selection of drug doses and/or intervals. The GFR increases with body size but does not increase in proportion to TBW. Instead, GFR increases in proportion to LBW and BSA. Two common equations used to estimate GFR rely on either BSA (MDRD) or weight (CG) to estimate absolute GFR (ml/min). However, current equations that rely on BSA overestimate GFR in obese individuals. Use of LBW overcomes this limitation and appears to be the most practical solution to the estimation of CLcr (as a surrogate of GFR) for drug dosing in obesity. References 1. World Health Organization: Obesity and Overweight. Available at: factsheets/fs311/en/index.html. Accessed January 22, Flegal KM, Carroll MD, Ogden CL, et al: Prevalence and trends in obesity among US adults, JAMA 303: , Hanley MJ, Abernethy DR, Greenblatt DJ: Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 49:71-87, Ogden CL, Fryar CD, Carroll MD, et al: Mean body weight, height, and body mass index, United States Adv Data 347:1-17, Mosteller RD: Simplified calculation of body-surface area. N Engl J Med 317:1098, Pi-Sunyer X: The medical risks of obesity. Postgrad Med 121:21-33, Griffin KA, Kramer H, Bidani AK: Adverse renal consequences of obesity. Am J Physiol Renal Physiol 294: F685-F696, Coresh J, Selvin E, Stevens LA, et al: Prevalence of chronic kidney disease in the United States. JAMA 298: , Tett SE, Kirkpatrick CM, Gross AS, et al: Principles and clinical application of assessing alterations in renal elimination pathways. Clin Pharmacokinet 42: , Verbeeck RK, Musuamba FT: Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol 65: , Lalonde RL, Wagner JA: Drug development perspective on pharmacokinetic studies of new drugs in patients with renal impairment. Clin Pharmacol Ther 86: , Guidance for Industry Population Pharmacokinetics. US Department of Health and Human Service. Food and Drug Administration February 1999

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