Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans

Bamfo, Nadia O.; Hosey-Cojocari, Chelsea; Benet, Leslie Z.; Remsberg, Connie M.

doi:10.1007/s11095-021-03076-y

Cited by 7 publications

(8 citation statements)

References 143 publications

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“…To address this question, we evaluated gentamicin and tobramycin because they have limited plasma protein binding, no known metabolism, and are eliminated unchanged (>90%) in urine, and so serve as exceptional probes of the GFR. 33 Our analyses show that the estimates These findings are consistent for many drugs that are eliminated unchanged in urine. For example, a recent population PK model of gabapentin showed that weight and kidney function accounted for 15% of the interindividual variability of the apparent CL (CL/F).…”

Section: Discussionsupporting

confidence: 72%

“…To address this question, we evaluated gentamicin and tobramycin because they have limited plasma protein binding, no known metabolism, and are eliminated unchanged (>90%) in urine, and so serve as exceptional probes of the GFR. 33 Our analyses show that the estimates of gentamicin and tobramycin CL across eGFRcr are not different in self‐identified Caucasians compared to African Americans. Most importantly, estimated kidney function can only account for a portion of the interindividual variability of aminoglycoside CL.…”

Section: Discussionmentioning

confidence: 63%

“…So can the removal of the race factor negatively impact our estimation of drug doses in the predominant population when using the revised 2021 CKD‐EPI eGFRcr equation? To address this question, we evaluated gentamicin and tobramycin because they have limited plasma protein binding, no known metabolism, and are eliminated unchanged (>90%) in urine, and so serve as exceptional probes of the GFR 33 . Our analyses show that the estimates of gentamicin and tobramycin CL across eGFRcr are not different in self‐identified Caucasians compared to African Americans.…”

Section: Discussionmentioning

confidence: 97%

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Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

2022

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Study Objective The use of race in medicine can contribute to health inequity. Updated equations for estimated glomerular filtration rate (eGFR) without race have been published. Likewise, de‐indexation of eGFR to body surface area (BSA) has been recommended by regulatory guidance for drug dosing in renal impairment. Clinical data justifying these recommendations for drug dosing are sparse. We examined the gain or loss of precision in drug dosing with estimated creatinine clearance (eCLcr) and eGFR using serum creatinine (eGFRcr) with and without race and BSA indexation by evaluating the population pharmacokinetics of the aminoglycosides as a classic drug class to probe kidney function. Design Medical records from adult patients treated with gentamicin or tobramycin over a 13‐year period were queried. Population pharmacokinetic analyses were performed using a 1‐compartment base structural model. Models compared body size descriptors as covariates of the volume of distribution (V). Estimated creatinine clearance and eGFRcr using multiple contemporary equations with and without BSA indexation were tested as covariates of clearance (CL). Main Results The final data set included 2968 patients treated with either gentamicin (20.2%) or tobramycin (79.8%). Patients self‐identified as Caucasian (82%), African‐American (10%), or other. The median [5th, 95th percentile] weight and BSA were 80.5 [49.4, 136] kg and 1.94 [1.48, 2.56] m2, respectively. Models of eCLcr and eGFRcr without indexation to BSA had a better model fit than eGFRcr indexed to BSA for aminoglycoside CL. The 2021 Chronic Kidney Disease Epidemiology collaboration (CKD‐EPI) eGFRcr equation (no race, no BSA indexation) provided a comparable model fit to the 2009 CKD‐EPI eGFRcr equation (with race, no BSA indexation) for aminoglycoside CL. Conclusions Race is not a relevant covariate of aminoglycoside CL. The 2021 CKD‐EPI eGFR equation without race and BSA indexation is a better method for gentamicin and tobramycin CL estimation. Confirmation of these results for other drugs can support the harmonization of dosing by kidney function.

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Section: Discussionsupporting

confidence: 72%

“…To address this question, we evaluated gentamicin and tobramycin because they have limited plasma protein binding, no known metabolism, and are eliminated unchanged (>90%) in urine, and so serve as exceptional probes of the GFR. 33 Our analyses show that the estimates of gentamicin and tobramycin CL across eGFRcr are not different in self‐identified Caucasians compared to African Americans. Most importantly, estimated kidney function can only account for a portion of the interindividual variability of aminoglycoside CL.…”

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 97%

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Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

2022

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“…Rodents (rats and mice) and non-rodents (monkeys) are the two types of animals that are most frequently employed in transporter-mediated DDI research [ 104 ]. Rodents, such as Sprague–Dawley rats, Wistar rats, and wild-type mice, have been widely utilized as the first species for pharmacokinetic studies because they are affordable, have good reproductive performance, and are resistant to infectious diseases [ 60 ].…”

Section: Methods For the Study Of Ddis Mediated By Renal Transportersmentioning

confidence: 99%

Research Methods and New Advances in Drug–Drug Interactions Mediated by Renal Transporters

et al. 2023

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The kidney is critical in the human body’s excretion of drugs and their metabolites. Renal transporters participate in actively secreting substances from the proximal tubular cells and reabsorbing them in the distal renal tubules. They can affect the clearance rates (CLr) of drugs and their metabolites, eventually influence the clinical efficiency and side effects of drugs, and may produce drug–drug interactions (DDIs) of clinical significance. Renal transporters and renal transporter-mediated DDIs have also been studied by many researchers. In this article, the main types of in vitro research models used for the study of renal transporter-mediated DDIs are membrane-based assays, cell-based assays, and the renal slice uptake model. In vivo research models include animal experiments, gene knockout animal models, positron emission tomography (PET) technology, and studies on human beings. In addition, in vitro–in vivo extrapolation (IVIVE), ex vivo kidney perfusion (EVKP) models, and, more recently, biomarker methods and in silico models are included. This article reviews the traditional research methods of renal transporter-mediated DDIs, updates the recent progress in the development of the methods, and then classifies and summarizes the advantages and disadvantages of each method. Through the sorting work conducted in this paper, it will be convenient for researchers at different learning stages to choose the best method for their own research based on their own subject’s situation when they are going to study DDIs mediated by renal transporters.

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“…The reasons for IVIVE “disconnects” are often initially unknown and might be understood only later, following mechanistic absorption, distribution, metabolism, excretion (ADME) assays, and quantification of disposition and elimination pathways in vivo. Typical examples are compounds liable to active hepatic uptake, active renal elimination, , and/or extrahepatic metabolism. , Efforts to deconvolute disconnected IVIVE are lengthy and costly, likely opposing our ambition to replace, reduce, and refine use of animal studies. Can we do better?…”

Section: Introductionmentioning

confidence: 99%

Drug Design and Success of Prospective Mouse In Vitro–In Vivo Extrapolation (IVIVE) for Predictions of Plasma Clearance (CL_p) from Hepatocyte Intrinsic Clearance (CL_int)

2023

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Hepatocyte intrinsic clearance (CLint) and methods of in vitro–in vivo extrapolation (IVIVE) are often used to predict plasma clearance (CLp) in drug discovery. While the prediction success of this approach is dependent on the chemotype, specific molecular properties and drug design features that govern these outcomes are poorly understood. To address this challenge, we investigated the success of prospective mouse CLp IVIVE across 2142 chemically diverse compounds. Dilution scaling, which assumes that the free fraction in hepatocyte incubations (f u,inc) is governed by binding to the 10% of serum in the incubation medium, was used as our default CLp IVIVE approach. Results show that predictions of CLp are better for smaller (molecular weight (MW) < 500 Da), less polar (total polar surface area (TPSA) < 100 Å2, hydrogen bond donor (HBD) ≤1, hydrogen bond acceptor (HBA) ≤ 6), lipophilic (log D > 3), and neutral compounds, with low HBD count playing the key role. If compounds are classified according to their chemical space, predictions were good for compounds resembling central nervous system (CNS) drugs [average absolute fold error (AAFE) of 2.05, average fold error (AFE) of 0.90], moderate for classical druglike compounds (according to Lipinski, Veber, and Ghose guidelines; AAFE of 2.55; AFE of 0.68), and poor for nonclassical “beyond the rule of 5” compounds (AAFE of 3.31; AFE of 0.41). From the perspective of measured druglike properties, predictions of CLp were better for compounds with moderate-to-high hepatocyte CLint (>10 μL/min/106 cells), high passive cellular permeability (P app > 100 nm/s), and moderate observed CLp (5–50 mL/min/kg). Influences of plasma protein binding (f u,p) and P-glycoprotein (Pgp) apical efflux ratio (AP-ER) were less pronounced. If the extended clearance classification system (ECCS) is applied, predictions were good for class 2 (P app > 50 nm/s; neutral or basic; AAFE of 2.35; AFE of 0.70) and acceptable for class 1A compounds (AAFE of 2.98; AFE of 0.70). Classes 1B, 3 A/B, and 4 showed poor outcomes (AAFE > 3.80; AFE < 0.60). Functional groups trending toward weaker CLp IVIVE were esters, carbamates, sulfonamides, carboxylic acids, ketones, primary and secondary amines, primary alcohols, oxetanes, and compounds liable to aldehyde oxidase metabolism, likely due to multifactorial reasons. Multivariate analysis showed that multiple properties are relevant, combining together to define the overall success of CLp IVIVE. Our results indicate that the current practice of prospective CLp IVIVE is suitable only for CNS-like compounds and well-behaved classical druglike space (e.g., high permeability or ECCS class 2) without challenging functional groups. Unfortunately, based on existing mouse data, prospective CLp IVIVE for complex and nonclassical chemotypes is poor and hardly better than random guessing. This is likely due to complexities such as extrahepatic metabolism and transporter-mediated disposition which are poorly captured by this methodology. With small-molecule drug discover...

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Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans

Cited by 7 publications

References 143 publications

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

Research Methods and New Advances in Drug–Drug Interactions Mediated by Renal Transporters

Drug Design and Success of Prospective Mouse In Vitro–In Vivo Extrapolation (IVIVE) for Predictions of Plasma Clearance (CL_p) from Hepatocyte Intrinsic Clearance (CL_int)

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Examination of Urinary Excretion of Unchanged Drug in Humans and Preclinical Animal Models: Increasing the Predictability of Poor Metabolism in Humans

Cited by 7 publications

References 143 publications

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

Removing race and body surface area indexation for estimated kidney function based drug dosing: Aminoglycosides as justification of these principles

Research Methods and New Advances in Drug–Drug Interactions Mediated by Renal Transporters

Drug Design and Success of Prospective Mouse In Vitro–In Vivo Extrapolation (IVIVE) for Predictions of Plasma Clearance (CLp) from Hepatocyte Intrinsic Clearance (CLint)

Contact Info

Product

Resources

About

Drug Design and Success of Prospective Mouse In Vitro–In Vivo Extrapolation (IVIVE) for Predictions of Plasma Clearance (CL_p) from Hepatocyte Intrinsic Clearance (CL_int)