Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450‐3A in drug–drug interaction studies

• Published in: British journal of clinical pharmacology Vol. 80; no. 3; pp. 342 - 350
• Main Authors: Greenblatt, David J., Harmatz, Jerold S.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.09.2015
• Subjects: Area Under Curve; clarithromycin; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - adverse effects; Cytochrome P-450 CYP3A Inhibitors - pharmacology; cytochrome P450‐3A; Drug Design; Drug Interactions; drug–drug interactions; Humans; itraconazole; ketoconazole; Ketoconazole - administration & dosage; Ketoconazole - adverse effects; Ketoconazole - pharmacology; Midazolam - administration & dosage; Midazolam - pharmacokinetics; ritonavir; Ritonavir - administration & dosage; Ritonavir - adverse effects; Ritonavir - pharmacology; Systematic Reviews; United States; United States Food and Drug Administration; United States; cytochrome P450-3A; ketoconazole; drug-drug interactions; itraconazole; clarithromycin; ritonavir
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12668

Aims The regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug–drug interaction (DDI) studies has compelled consideration of alternative inhibitors. Methods The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. Results Mean (± SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre‐exposure prior to administration of MDZ. Conclusions Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP3A inhibitor alternative to ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with ketoconazole or ritonavir, and have other significant disadvantages as well.