title: PBPK model describes the effects of comedication and genetic polymorphism on systemic exposure of drugs that undergo multiple clearance pathways.
abstract: An important goal in drug development is to understand the effects of intrinsic and/or extrinsic factors (IEFs) on drug pharmacokinetics. Although clinical studies investigating a given IEF can accomplish this goal, they may not be feasible for all IEFs or for situations when multiple IEFs exist concurrently. Physiologically based pharmacokinetic (PBPK) models may serve as a complementary tool for forecasting the effects of IEFs. We developed PBPK models for four drugs that are eliminated by both cytochrome P450 (CYP)3A4 and CYP2D6, and evaluated model prediction of the effects of comedications and/or genetic polymorphism on drug exposure. PBPK models predicted 100 and ≥70% of the observed results when the conventional "twofold rule" and the more conservative 25% deviation cut point were applied, respectively. These findings suggest that PBPK models can be used to infer effects of individual or combined IEFs and should be considered to optimize studies that evaluate these factors, specifically drug interactions and genetic polymorphism of drug-metabolizing enzymes.
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: M D L T
authors.initials: MD
authors.lastname: Vieira
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: S
authors.initials: S
authors.lastname: Apparaju
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sinha
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US 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, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: S-M
authors.initials: SM
authors.lastname: Huang
authors.affiliation: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhao
mesh_terms: D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic
chemical_list: D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human