title: Quantitative Prediction of Drug-Drug Interactions Involving Inhibitory Metabolites in Drug Development: How Can Physiologically Based Pharmacokinetic Modeling Help?
abstract: This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug-drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent-metabolite pairs is described and guidance on strategic application is provided.
authors.affiliation: Genentech, South San Francisco, California, USA. templeton.ian@gene.com.
authors.forename: I E
authors.initials: IE
authors.lastname: Templeton
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Genentech, South San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mao
authors.affiliation: Pfizer Inc., Groton, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.affiliation: AstraZeneca, Mölndal, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Peters
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shebley
authors.affiliation: Pfizer Inc., Groton, Connecticut, USA. manthena.v.varma@pfizer.com.
authors.forename: M V
authors.initials: MV
authors.lastname: Varma
mesh_terms: D000638:Amiodarone / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D055808:Drug Discovery; D004347:Drug Interactions; D015248:Gemfibrozil / Q000493:pharmacokinetics*; D006801:Humans; D008954:Models, Biological; D020280:Sertraline / Q000493:pharmacokinetics*
chemical_list: D000638:Amiodarone; D015248:Gemfibrozil; D020280:Sertraline