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

Abstract

AIMSThe regulatory prohibition of ketoconazole as a CYP3A index inhibitor in drug-drug interaction (DDI) studies has compelled consideration of alternative inhibitors. METHODSThe 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 (R AUC ) 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. RESULTSMean (± SE) R AUC 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). R AUC values were not significantly related to inhibitor dosage or to duration of inhibitor preexposure prior to administration of MDZ. CONCLUSIONSRitonavir 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.

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

“…The remaining singledrug alternatives include clarithromycin, ritonavir, and itraconazole (Ke et al, 2014;Greenblatt and Harmatz, 2015); therefore, the data presented in this work were limited to a comparison of these drugs with ketoconazole regarding their impact on the most important drug transporters. The major metabolites of itraconazole were also included because 40-50% of the overall impact on CYP3A4/5 after multiple dosing is attributable to these metabolites (Ke et al, 2014).…”

“…The FDA specifically recommended the use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors for use in clinical DDI studies, but further noted that investigators may suggest other CYP3A4/5 inhibitors (FDA, 2013a). In addition to itraconazole and clarithromycin, ritonavir has also been suggested by some authors as a possible alternative to ketoconazole (Greenblatt and Greenblatt, 2014;Greenblatt, 2015;Greenblatt and Harmatz, 2015), but excluded by others on the basis of nonspecific CYP inhibition or induction (Ke et al, 2014;Liu et al, 2015).…”

Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers

“…A number of alternative index CYP3A inhibitors have been proposed, for use in DDI studies. Itraconazole and clarithromycin have been proposed, but do not produce in vivo CYP3A inhibition comparable to ketoconazole . Itraconazole is associated with incidence rates of hepatic injury similar to ketoconazole .…”

Pharmacokinetic/pharmacodynamic drug–drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs

“…In contrast, a strong CYP3A inhibitor, itraconazole had milder effects on the avatrombopag PK and PD than those of fluconazole. Even though inhibition by itraconazole is known less than the extent of inhibition produced by ketoconazole , considering together with PBPK simulation results (Appendix S2), ketoconazole would also indicate milder effects on the avatrombopag than those of fluconazole. As itraconazole is known to have no impact on CYP2C9 activity , the substantial impact of fluconazole suggests that CYP2C9 plays a more dominant role in metabolic clearance of avatrombopag than CYP3A.…”