Simple Evaluation Method for CYP3A4 Induction from Human Hepatocytes: The Relative Factor Approach with an Induction Detection Limit Concentration Based on the E-max Model

摘要

We investigated the robustness and utility of the relative factor (RF) approach based on the maximum induction effect (E-max) model, using the mRNA induction data of 10 typical CYP3A4 inducers in cryopreserved human hepatocytes. The RF value is designated as the ratio of the induction detection limit concentration (IDLC) for a standard inducer, such as rifampicin (RIF) or phenobarbital (PB), to that for the compound (e.g., RFRIF is IDLCRIF/IDLCcpd; RFPB is IDLCPB/IDLCcpd). An important feature of the RF approach is that the profiles of the induction response curves on the logarithmic scale remain unchanged irrespective of inducers but are shifted parallel depending on the EC50 values. A key step in the RF approach is to convert the induction response curve by finding the IDLC of a standard inducer. The relative induction score was estimated not only from E-max and EC50 values but also from those calculated by the RF approach. These values showed good correlation, with a correlation coefficient of more than 0.974, which revealed the RF approach to be a robust analysis irrespective of its simplicity. Furthermore, the relationship between RFRIF or RFPB multiplied by the steady-state unbound plasma concentration and the in vivo induction ratio plotted using 10 typical inducers gives adequate thresholds for CYP3A4 drugdrug interaction risk assessment. In light of these findings, the simple RF approach using the IDLC value could be a usefulmethod to adequately assess the risk of CYP3A4 induction in humans during drug discovery and development without evaluation of E-max and EC50.