title: Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mRNA induction data.
abstract: Several drug-drug interaction (DDI) prediction models were evaluated for their ability to identify drugs with cytochrome P450 (CYP)3A induction liability based on in vitro mRNA data. The drug interaction magnitudes of CYP3A substrates from 28 clinical trials were predicted using (i) correlation approaches (ratio of the in vivo peak plasma concentration (Cmax) to in vitro half-maximal effective concentration (EC50); and relative induction score), (ii) a basic static model (calculated R3 value), (iii) a mechanistic static model (net effect), and (iv) mechanistic dynamic (physiologically based pharmacokinetic) modeling. All models performed with high fidelity and predicted few false negatives or false positives. The correlation approaches and basic static model resulted in no false negatives when total Cmax was incorporated; these models may be sufficient to conservatively identify clinical CYP3A induction liability. Mechanistic models that include CYP inactivation in addition to induction resulted in DDI predictions with less accuracy, likely due to an overprediction of the inactivation effect.
authors.affiliation: Novartis, East Hanover, New Jersey, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Einolf
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Pfizer, Groton, Connecticut, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Fahmi
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Gibson
authors.affiliation: Pfizer, Groton, Connecticut, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Obach
authors.affiliation: AbbVie Inc, North Chicago, Illinois, USA.
authors.forename: M
authors.initials: M
authors.lastname: Shebley
authors.affiliation: Johnson & Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Silva
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Sinz
authors.affiliation: University of Washington, Seattle, Washington, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Unadkat
authors.affiliation: US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: US Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhao
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human