Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies.
OBJECTIVE
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.
From the Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA, USA.
David J
DJ
Greenblatt
From the Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Sackler School of Graduate Biomedical Sciences, Boston, MA, USA.
Jerold S
JS
Harmatz
D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014481:United States; D014486:United States Food and Drug Administration
D065692:Cytochrome P-450 CYP3A Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir; D008874:Midazolam; D007654:Ketoconazole
clarithromycin; cytochrome P450-3A; drug-drug interactions; itraconazole; ketoconazole; ritonavir