Evaluation of Time-Dependent CYP3A4 Inhibition Using Human Hepatocytes

Time-dependent inhibition (TDI) is an important consideration in the drug development process. To date, methods to accurately predict the magnitude of a clinical interaction from pre-clinical TDI data have been lacking. Although more complex prediction algorithms have been developed, the accuracy has still improved little. This suggests alternate methods to collect input data may improve prediction robustness. Historically, human liver microsomes have been used to generate inhibition kinetic data used as inputs in the in vivo DDI predictions. Recently, it has been suggested that human hepatocytes and the kinetic data derived from this matrix may provide a better prediction for assessing clinical interactions related to TDI. This chapter reviews a detailed method to assess TDI related to CYP3A in human hepatocytes.