Application of unbound liver-to-plasma concentration ratio to quantitative projection of cytochrome P450-mediated drug-drug interactions using physiologically based pharmacokinetic modelling approach.

1. This study evaluated the prediction accuracy of cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) using minimal physiologically-based pharmacokinetic (PBPK) modelling incorporating the hepatic accumulation factor of an inhibitor (i.e. unbound liver/unbound plasma concentration ratio [K]) based on 22 clinical DDI studies. 2. K values were estimated using three methods: (1) ratio of cell-to-medium ratio in human cryopreserved hepatocytes (C/M) at 37 °C to that on ice (K), (2) multiplication of total liver/unbound plasma concentration ratio (K) estimated from C/M at 37 °C with unbound fraction in human liver homogenate (K) and (3) observed K in rats after intravenous infusion (K). 3. PBPK model using each K projected the area under the curve (AUC) increase of substrates more accurately than the model assuming a K of 1 for the average fold error and root mean square error did. Particularly, the model with a K of 1 underestimated the AUC increase of triazolam following co-administration with CYP3A4 inhibitor itraconazole by five-fold, whereas the AUC increase projected using the model incorporating the K, K, or K of itraconazole and hydroxyitraconazole was within approximately two-fold of the actual value. 4. The results indicated that incorporating K into the PBPK model improved the accuracy of DDI projection.