Evaluation of calibration curve-based approaches to predict clinical inducers and noninducers of CYP3A4 with plated human hepatocytes.

Cytochrome P450 (P450) induction is often considered a liability in drug development. Using calibration curve-based approaches, we assessed the induction parameters R3 (a term indicating the amount of P450 induction in the liver, expressed as a ratio between 0 and 1), relative induction score, Cmax/EC50, and area under the curve (AUC)/F2 (the concentration causing 2-fold increase from baseline of the dose-response curve), derived from concentration-response curves of CYP3A4 mRNA and enzyme activity data in vitro, as predictors of CYP3A4 induction potential in vivo. Plated cryopreserved human hepatocytes from three donors were treated with 20 test compounds, including several clinical inducers and noninducers of CYP3A4.

A multi-endpoint evaluation of cytochrome P450 1A2, 2B6 and 3A4 induction response in human hepatocyte cultures after treatment with β-naphthoflavone, phenobarbital and rifampicin.

U.S. FDA and EMEA guidance recommend that the preferred in vitro model for cytochrome P450 induction testing is human hepatocytes coupled with acceptable inducers as controls.