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

• Published in: Clinical pharmacology in drug development 2015-01, Vol.4 (1), p.25-32
• Main Authors: Barve, Avantika, Kovacs, Steven J., Ke, June, Crabbe, Rafael, Grosgurin, Peter, Menetrey, Annick, Nicolas-Métral, Valerie, Dabovic, Kristina, Dole, Kiran, Zhang, Jie, Praestgaard, Jens, Sunkara, Gangadhar, Stein, Daniel
• Format: Article
• Language: English
• Subjects: alisporivir; Area Under Curve; Azithromycin - administration & dosage; Azithromycin - adverse effects; Belgium; Biotransformation; Cross-Over Studies; Cyclosporine - administration & dosage; Cyclosporine - adverse effects; Cyclosporine - blood; Cyclosporine - pharmacokinetics; CYP3A4; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inducers - administration & dosage; Cytochrome P-450 CYP3A Inducers - adverse effects; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - adverse effects; Drug Interactions; drug-drug interaction; Female; Florida; Half-Life; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Ketoconazole - administration & dosage; Ketoconazole - adverse effects; Male; Metabolic Clearance Rate; Models, Biological; New York; pharmacokinetics; Rifampin - administration & dosage; Rifampin - adverse effects; Substrate Specificity
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.114

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 Cmax, 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 Cmax and AUC of alisporivir. Rifampin (a CYP3A4 inducer) caused an approximate 90% reduction in alisporivir Cmax and AUC and a fourfold reduction in alisporivir terminal elimination half‐life. 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.