Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Kristin E Follman, Marilyn E Morris

Abstract

Renal impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiologic changes, in addition to a decrease in glomerular filtration rate, that impact the pharmacokinetics (PK) and, specifically, the renal clearance (CLR) of compounds, including alterations of drug transporter (DT)/drug-metabolizing enzyme expression and activity, as well as protein binding. The objectives of this study were to use a physiologically based pharmacokinetic modeling platform to 1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs), and free fraction (fu) on PK predictions for the organic cation transporter 2/multidrug and toxin extrusion protein 1 substrate metformin in RI populations; and 2) use available in vitro data to improve predictions of CLR for two actively secreted substrates, metformin and ranitidine. The goal was to identify changes in parameters other than glomerular filtration rate-namely, fu and DT expression/activity-that are consistent with in vitro and clinical data in RI, and predict the importance of these parameters in the PK of metformin and ranitidine in RI patients. Our results demonstrated that including alterations in DT expression and fu, and including TDIs...Continue Reading

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Citations

Apr 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qingcheng MaoJoanne Wang
Nov 19, 2020·Journal of Clinical Pharmacology·Paul R V MalikAndrea N Edginton

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