Abstract

A great deal of effort has been being made to improve the accuracy of the prediction of drug-drug interactions (DDIs). In this study, we addressed cytochrome P450 (CYP) 3A-mediated weak DDI where a relatively high false prediction rate was pointed out. We selected 17 orally administered drugs which have been reported to alter area under the curve (AUC) of midazolam, a typical CYP3A substrate, 0.84-1.47 times. For weak CYP3A perpetrators, the predicted AUC ratio mainly depends on intestinal DDIs rather than hepatic DDIs, as the drug concentration in the enterocytes is higher. Thus, DDI prediction using simulated concentration-time profiles in each segment of the digestive tract was made by physiologically based pharmacokinetic (PBPK) modeling software GastroPlus®. While mechanistic static models tend to overestimate the risk to ensure the safety of patients, some underestimation is reported about PBPK modeling. Our in vitro studies revealed that 16 out of 17 tested drugs exhibited time-dependent inhibition (TDI) of CYP3A, and the subsequent DDI simulation that ignored these TDIs provided false-negative results. This is considered to be the cause of past underestimation. Inclusion of the DDI parameters of all the known DDI mechanisms, reversible inhibition and TDI, and induction, which have opposite effects on midazolam AUC, to PBPK model was successful in improving predictability of the DDI without increasing false negative prediction as trade-off. This comprehensive model-based analysis suggests the importance of the intestine in assessing weak DDIs via CYP3A and the usefulness of PBPK in predicting intestinal DDIs.