Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

Yoshida, K.; Sun, B.; Zhang, L.; Zhao, P.; Abernethy, DR; Nolin, TD; Rostami-Hodjegan, A.; Zineh, I.; Huang, S-M

doi:10.1002/cpt.337

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

Journal Article · Mon Mar 07 00:00:00 UTC 2016 · Clinical Pharmacology and Therapeutics

DOI:https://doi.org/10.1002/cpt.337· OSTI ID:1623522

Yoshida, K. ^[1]; Sun, B. ^[2]; Zhang, L. ^[3]; Zhao, P. ^[3]; Abernethy, DR ^[3]; Nolin, TD ^[4]; Rostami-Hodjegan, A. ^[5]; Zineh, I. ^[6]; Huang, S-M ^[3]

U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Translational Sciences. Office of Clinical Pharmacology; DOE/OSTI
U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Translational Sciences. Office of Clinical Pharmacology; Shanghai Jiao Tong Univ. (China). School of Medicine. Shanghai General Hospital. Dept. of Pharmacy
U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Translational Sciences. Office of Clinical Pharmacology
Univ. of Pittsburgh, PA (United States). Schools of Pharmacy and Medicine. Dept. of Medicine Renal-Electrolyte Division. Dept. of Pharmacy and Therapeutics. Center for Clinical Pharmaceutical Sciences
Univ. of Manchester (United Kingdom). Manchester Pharmacy School. Centre for Applied Pharmaceutical Research; Simcyp (a Certara Company), Sheffield (United Kingdom)
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring Maryland USA

Recent reviews suggest that chronic kidney disease (CKD) can affect the pharmacokinetics of nonrenally eliminated drugs, but the impact of CKD on individual elimination pathways has not been systematically evaluated. In this study we developed a comprehensive dataset of the effect of CKD on the pharmacokinetics of CYP2D6- and CYP3A4/5-metabolized drugs. Drugs for evaluation were selected based on clinical drug–drug interaction (CYP3A4/5 and CYP2D6) and pharmacogenetic (CYP2D6) studies. Information from dedicated CKD studies was available for 13 and 18 of the CYP2D6 and CYP3A4/5 model drugs, respectively. Analysis of these data suggested that CYP2D6-mediated clearance is generally decreased in parallel with the severity of CKD. There was no apparent relationship between the severity of CKD and CYP3A4/5-mediated clearance. The observed elimination-route dependency in CKD effects between CYP2D6 and CYP3A4/5 may inform the need to conduct clinical CKD studies with nonrenally eliminated drugs for optimal use of drugs in patients with CKD.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1623522

Journal Information:: Clinical Pharmacology and Therapeutics, Journal Name: Clinical Pharmacology and Therapeutics Journal Issue: 1 Vol. 100; ISSN 0009-9236

Publisher:: American Society for Clinical Pharmacology & Therapeutics - WileyCopyright Statement

Country of Publication:: United States

Language:: English

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