Scientific Publications by FDA Staff
Clin Pharmacol Ther 2014 Feb;95(2):189-98
Evaluation of Various Static In vitro-In vivo Extrapolation Models for Risk Assessment of CYP3A Inhibition Potential of an Investigational Drug.
Vieira M, Kirby B, Ragueneau-Majlessi I, Galetin A, Chien J, Einolf H, Fahmi O, Fischer V, Fretland A, Grime K, Hall S, Higgs R, Plowchalk D, Riley R, Seibert E, Skordos K, Snoeys J, Venkatakrishnan K, Waterhouse T, Obach R, Berglund E, Zhang L, Zhao P, Reynolds K, Huang SM
Nine static models (7 basic, 2 mechanistic) and their respective cut-off values used for predicting CYP3A inhibition, as recommended by the US-FDA and EMA, were evaluated using data from 119 clinical studies with orally-administered midazolam as substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%); while those using intestinal luminal [I]gut 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. Therefore, when mechanistic models are used to predict the likelihood of CYP3A inhibition, a cut-off of 1.25-fold change in AUC is recommended.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 15 September 2013 doi:10.1038/clpt.2013.187.
|Category: Journal Article|
|PubMed ID: #24048277||DOI: 10.1038/clpt.2013.187|
|Includes FDA Authors from Scientific Area(s): Drugs|
|Entry Created: 2013-09-21||Entry Last Modified: 2014-02-22|