Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.

Autor: Vieira ML; US Food and Drug Administration, Silver Spring, MD, USA., Kirby B; University of Washington, Seattle, WA, USA., Ragueneau-Majlessi I; University of Washington, Seattle, WA, USA., Galetin A; University of Manchester, Greater Manchester, UK., Chien JY; Eli Lilly and Company, Indianapolis, IN, USA., Einolf HJ; Novartis, East Hanover, NJ, USA., Fahmi OA; Pfizer Inc., Groton, CT, USA., Fischer V; AbbVie, North Chicago, IL, USA., Fretland A; Eli Lilly and Company, Indianapolis, IN, USA., Grime K; AstraZeneca Research and Development, Mölndal, Sweden., Hall SD; Eli Lilly and Company, Indianapolis, IN, USA., Higgs R; Eli Lilly and Company, Indianapolis, IN, USA., Plowchalk D; Pfizer Inc., Groton, CT, USA., Riley R; AstraZeneca Research and Development, Alderley Park, UK., Seibert E; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA., Skordos K; GlaxoSmithKline, Research Triangle Park, NC, USA., Snoeys J; Janssen Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium., Venkatakrishnan K; Millennium Pharmaceuticals, Cambridge, MA, USA., Waterhouse T; Eli Lilly and Company, Indianapolis, IN, USA., Obach RS; Pfizer Inc., Groton, CT, USA., Berglund EG; Medical Products Agency, Uppsala, Sweden., Zhang L; US Food and Drug Administration, Silver Spring, MD, USA., Zhao P; US Food and Drug Administration, Silver Spring, MD, USA., Reynolds KS; US Food and Drug Administration, Silver Spring, MD, USA., Huang SM; US Food and Drug Administration, Silver Spring, MD, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2014 Feb; Vol. 95 (2), pp. 189-98. Date of Electronic Publication: 2013 Sep 18.
DOI: 10.1038/clpt.2013.187
Abstrakt: 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.
Databáze: MEDLINE
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