Simulation of Clinical Drug-drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Rifampin and carbamazepine have been recommended in the U.S. Food and Drug Administration draft drug interaction guidance as CYP3A4 inducers for clinical drug-drug interaction (DDI) studies. To optimize the dose regimens of these inducers for use in DDI studies, their effect at various doses and dosing durations on the area under the curve (AUC) of multiple probe substrates was simulated using a population-based simulator. A similar assessment of the inducer phenobarbital was also conducted. CYP3A4 induction by all three inducers was previously determined in hepatocytes, and the results were incorporated into simulations. The pharmacokinetics of the three inducers and their associated CYP3A4 drug interactions were predicted and compared with in vivo observations. The predicted Cmax and AUC of all the inducers and substrates correlated closely with those observed clinically. The predicted magnitudes of the DDIs caused by CYP3A4 induction were also in good agreement with the observed clinical results. Comparison of the maximal CYP3A4 induction potential among the three inducers indicated that rifampin is the most potent inducer and is the best choice for clinical CYP3A4 induction DDI studies. Moreover, a near-maximal CYP3A4 DDI was predicted to result from administration of rifampin for approximately 7 days at 450 to 600 mg q.d. or 200 to 300 mg b.i.d. These results suggest optimal dose regimens for clinical trials that maximize the probability of detecting a DDI caused by CYP3A4 induction. The simulation strategy provides the means to predict the induction profiles of compounds in development.