D. J. Greenblatt; Tufts University School of Medicine, Boston, MA
BACKGROUND: The US FDA prohibition against use of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has raised questions regarding alternative inhibitors that might produce CYP3A inhibition comparable to ketoconazole.
METHODS: The literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either ketoconazole (KETO), itraconazole (ITRA), clarithromycin (CLAR), or ritonavir (RIT). For each study, the AUC ratio (RAUC), defined as MDZ AUC with inhibitor divided by MDZ AUC in the control state, was determined. RAUC values were aggregated across studies for each inhibitor.
RESULTS: Mean (± SE) RAUC values were as follows: KETO (15 studies, 131 subjects), 11.5 ( ±1.2); ITRA (4 studies, 42 subjects), 7.3 (±1.1); CLAR (5 studies, 73 subjects), 6.2 (± 1.8); RIT (8 studies, 121 subjects), 12.8 (±2.4). Differences among inhibitors were significant (Chi-square = 3.78, p < 0.03).
CONCLUSION: RIT produces CYP3A inhibition, measured as inhibition of oral MDZ clearance, equivalent to or greater than KETO. ITRA and CLAR are not suitable alternatives since they do not produce inhibition comparable to KETO or RIT. RIT is the best alternative to KETO as an index CYP3A inhibitor for DDI studies. Cobicistat, a close structural analogue of RIT, produces inhibition comparable to RIT. Cobicistat is not available as a sole entity in the US.