Prediction of Drug-Drug Interactions based on Time-Dependent Inhibition from High Throughput Screening of Cytochrome P450 3A4 Inhibition

抄録

  A method of assessing the risk of drug-drug interaction (DDI) caused by mechanism-based inhibition (MBI) was developed for early-stage drug development using cytochrome P450 (CYP) 3A4 inhibition screening data. CYP3A4 inhibition was evaluated using a fluorescent substrate with or without preincubation containing an inhibitor. The results showed that five well-known mechanism-based inhibitors, but not the competitive inhibitor ketoconazole, had lower IC₅₀ after preincubation, suggesting the utility of the IC₅₀ shift by preincubation to discern mechanism-based inhibitors. A method to approximately predict the change in the area under the concentration-time curve (AUC) of a co-administered drug by MBI was found using IC₅₀ shift data and the unbound mean plasma concentration of the inhibitor. From our predictions of change in the AUC for 38 drugs using this method, all mechanism-based inhibitors causing change in the AUC of more than 200% were predicted to be high risk. In conclusion, our method provides a simple assessment of the risk of DDI from mechanism-based inhibitors, especially in the early stages of drug development.