title: Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5.
abstract: 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.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.|Department of Pharmacy, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P. R. China.
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Abernethy
authors.affiliation: Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, and Department of Medicine Renal-Electrolyte Division, University of Pittsburgh Schools of Pharmacy and Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Nolin
authors.affiliation: Centre for Applied Pharmaceutical Research, Manchester Pharmacy School, University of Manchester, Manchester, UK.|Simcyp (a Certara Company), Sheffield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: I
authors.initials: I
authors.lastname: Zineh
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: S-M
authors.initials: SM
authors.lastname: Huang
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D012720:Severity of Illness Index
chemical_list: D004364:Pharmaceutical Preparations; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human