title: Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.
abstract: Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate.
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Md L T
authors.initials: ML
authors.lastname: Vieira
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Kirby
authors.affiliation: University of Washington, Seattle, WA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Ragueneau-Majlessi
authors.affiliation: University of Manchester, Greater Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Galetin
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: J Y L
authors.initials: JY
authors.lastname: Chien
authors.affiliation: Novartis, East Hanover, NJ, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Einolf
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Fahmi
authors.affiliation: AbbVie, North Chicago, IL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Fischer
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fretland
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Grime
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Higgs
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Plowchalk
authors.affiliation: AstraZeneca Research and Development, Alderley Park, UK.
authors.forename: R
authors.initials: R
authors.lastname: Riley
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: E
authors.initials: E
authors.lastname: Seibert
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Skordos
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Millennium Pharmaceuticals, Cambridge, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Venkatakrishnan
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: T
authors.initials: T
authors.lastname: Waterhouse
authors.affiliation: Pfizer Inc., Groton, CT, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Obach
authors.affiliation: Medical Products Agency, Uppsala, Sweden.
authors.forename: E G
authors.initials: EG
authors.lastname: Berglund
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhao
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Reynolds
authors.affiliation: US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: S-M
authors.initials: SM
authors.lastname: Huang
mesh_terms: D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D018570:Risk Assessment
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D015507:Drugs, Investigational; D008874:Midazolam