ケトコナゾールによるラパチニブ代謝阻害の定量的予測

抄録

Lapatinib (LAP) is metabolized mainly by CYP3A4/5 and this metabolic pathway is inhibited by ketoconazole (KTZ), a strong CYP3A4 inhibitor. LAP is not only a substrate of CYP3A4, but also an inhibitor. It is known that the inhibition by LAP is a mechanism-based inhibition (MBI) as well as a competitive inhibition. We have reported the intestinal transit, absorption and metabolism-based pharmacokinetic (ITAM-PK) model, which can predict bioavailability (F) and drug-drug interactions quantitatively based on the in vitro metabolic and transport parameters. In this study, we aimed to predict F of LAP and KTZ, and also interactions of these drugs quantitatively.

Predicted F values with an ITAM-PK model were 0.0526 and 0.825 for LAP and KTZ, respectively. We also calculated CL_tot/F using the predicted F and the total body clearance obtained with an ITAM-PK model. The calculated CL_tot/F values for LAP and KTZ were consistent with those reported in humans. The AUC of LAP was calculated using an ITAM-PK model with or without KTZ co-administration. Predicted AUC increase of LAP by KTZ co-administration was similar to that reported in humans. The results demonstrated that the drug-drug interactions between LAP and KTZ can be quantitatively predicted in vitro using an ITAM-PK model.