The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling

Abstract

Purpose: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable.

Method: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values. The AUC ratios predicted by the PBPK model using in vivo Ki values were compared with those by the conventional method assuming constant inhibitor concentration.

Results: The in vivo Ki values of 11 inhibitors were estimated. When the in vivo Ki values became relatively lower, the in vitro Ki values were overestimated. This discrepancy between in vitro and in vivo Ki values became larger with an increase in lipophilicity. The prediction from the PBPK model involving the time profile of the inhibitor concentration was more accurate than the prediction by the conventional methods.

Conclusion: A discrepancy between the in vivo and in vitro Ki values was observed. The prediction using in vivo Ki values and the PBPK model was more accurate than the conventional methods.