HUMAN HEPATOCYTE INDUCTION STUDIES TO EVALUATE POTENTIAL OF CYP3A4 INDUCTION IN VIVO: TWENTY COMPOUNDS WITH THREE DONORS

Abstract

Recent guidance from regulatory agencies advocates the use of human hepatocytes as the test system for evaluating cytochrome P450 induction potential of drug candidates. The use of hepatocytes which have been prequalified for response to known clinical inducers and non‐inducers are indicated. In addition, the use of mRNA alone is suggested as the necessary endpoint to evaluate induction response. However, the applicability of using prequalified hepatocytes as the test system, and the use of mRNA alone as a response endpoint, has not been widely demonstrated. To this end, we have examined the induction response from a set of 20 model compounds which includes established clinical inducers and non‐inducers of CYP3A4/5, in cryopreserved hepatocytes from three donors. Endpoints examined were CYP3A4 mRNA and testosterone 6ß‐hydroxylase activity, typically over 8 concentration points to enable calculation of EC50 and Emax. Results were used to determine relative induction scores (RIS), R3 values, and fold‐induction threshold values that may classify a drug candidate as a potential clinical inducer. The results and merits of these and other parameters for evaluating induction potential of drug candidates will be discussed.