Volume 103, Issue 3 p. 485-492
Articles

PBPK Modeling of the Effect of Reduced Kidney Function on the Pharmacokinetics of Drugs Excreted Renally by Organic Anion Transporters

C-H Hsueh

C-H Hsueh

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

Oak Ridge Institute for Science and Education (ORISE) Fellow, Oak Ridge, Tennessee, USA

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V Hsu

V Hsu

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

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P Zhao

Corresponding Author

P Zhao

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

Correspondence: P Zhao ([email protected])Search for more papers by this author
L Zhang

L Zhang

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

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KM Giacomini

KM Giacomini

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA

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S-M Huang

S-M Huang

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA

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First published: 24 July 2017
Citations: 60

Abstract

Altered pharmacokinetics (PK) in subjects with chronic kidney disease (CKD) may lead to dosing adjustment of certain drugs in subjects with CKD. It can be valuable to quantitatively predict PK in CKD for the management of drug dosing in these subjects. We developed physiologically based pharmacokinetic (PBPK) models of seven renally eliminated drugs: adefovir, avibactam, entecavir, famotidine, ganciclovir, oseltamivir carboxylate, and sitagliptin. These drugs are all substrates of renal organic anion transporters (OATs). Drug models verified using PK data from healthy subjects (HS) were coupled with physiological models representing CKD that incorporated prior knowledge of effects of CKD on hepatic and renal elimination. The models reasonably described clinically observed PK changes in subjects with CKD (compared to subjects with normal renal function), with predicted AUC changes within 50% of the observed changes. PBPK models can be used to prospectively predict PK of renally eliminated OAT substrates in subjects with CKD.

CONFLICT OF INTEREST/DISCLOSURE

The authors declared no conflict of interest. The views expressed in this article do not necessarily reflect the official policies nor endorsements of the Department of Health and Human Services.