The effects of CYP3A4 induction and inhibition on the pharmacokinetics of alisporivir in humans

In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the C-max, AUC and terminal elimination half-life of alisporivir by approximately two-, eight-, and threefold, respectively. Co-administration with azithromycin (a putative weak CYP3A4 inhibitor and substrate) had no impact on the C-max and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir C-max and AUC and a fourfold reduction in alisporivir terminal elimination halflife. Alisporivir as an inhibitor of CYP3A4 caused a 39% increase in azithromycin exposure. The results from these studies establish alisporivir as a sensitive CYP3A4 substrate in vivo. Consequently, co-administered potent CYP3A4 inhibitors and inducers are likely to cause clinically significant changes in the exposure to alisporivir.