title: FDA evaluations using in vitro metabolism to predict and interpret in vivo metabolic drug-drug interactions: impact on labeling.
abstract: Recent advances in in vitro metabolism methods have led to an improved ability to predict clinically relevant metabolic drug-drug interactions. To address the relationships of in vitro metabolism data and in vivo metabolism outcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, Food and Drug Administration, evaluated a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data in (1) predicting in vivo drug-drug interactions, (2) determining the need to conduct an in vivo drug-drug interaction study, and (3) incorporating findings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vivo results, and (2) in vitro data were not predictive of in vivo results. Discussion of these cases highlights factors limiting predictability of in vivo metabolic interactions from in vitro metabolism data. The integration of these findings into drug product labeling is also discussed.
authors.affiliation: Office of Clinical Pharmacology and Biopharmaceutics, Food and Drug Administration, Rockville, MD 20852, USA.
authors.forename: B
authors.initials: B
authors.lastname: Davit
authors.forename: K
authors.initials: K
authors.lastname: Reynolds
authors.forename: R
authors.initials: R
authors.lastname: Yuan
authors.forename: F
authors.initials: F
authors.lastname: Ajayi
authors.forename: D
authors.initials: D
authors.lastname: Conner
authors.forename: E
authors.initials: E
authors.lastname: Fadiran
authors.forename: B
authors.initials: B
authors.lastname: Gillespie
authors.forename: C
authors.initials: C
authors.lastname: Sahajwalla
authors.forename: S M
authors.initials: SM
authors.lastname: Huang
authors.forename: L J
authors.initials: LJ
authors.lastname: Lesko
mesh_terms: D003625:Data Collection; D004347:Drug Interactions; D004348:Drug Labeling / Q000331:legislation & jurisprudence*; D006801:Humans; D066298:In Vitro Techniques; D008660:Metabolism / Q000502:physiology*; D008954:Models, Biological; D010600:Pharmacology; D011237:Predictive Value of Tests; D013223:Statistics as Topic; D014116:Toxicology; D014481:United States; D014486:United States Food and Drug Administration