Evidence‐based choice of ritonavir as index CYP3A inhibitor in drug‐drug interaction studies

Abstract

The "index" cytochrome P450-3A (CYP3A) inhibitor has become a critical research tool for the process of drug development.1,2 If a candidate drug under development is suspected of being dependent on CYP3A for its clearance, coadministration of this candidate with a strong or maximal in vivo CYP3A inhibitor can validate the relative contribution of CYP3A to net clearance, and map out the "worst possible" drug-drug interaction (DDI) scenario when CYP3A activity is essentially nullified. If the candidate itself is suspected of being a CYP3A inhibitor, its quantitative in vivo inhibitory potency can be compared to the "worst possible" extreme if the index inhibitor is used as a positive control in a DDI study involving a sensitive CYP3A substrate.The azole antifungal agent ketoconazole has served as the prototype index CYP3A inhibitor in this context for many years. 2,3 Ketoconazole has the following specific favorable attributes: (1) usual clinical doses (400 mg per day) will produce the maximum possible CYP3A inhibition in vivo; (2) these doses carry minimal risk of adverse events in healthy volunteers; (3) less than 24 hours of preexposure to ketoconazole is needed to produce maximal CYP3A inhibition, and a loading dose is not required; (4) inhibition is relatively (although not absolutely) specific for CYP3A; (5) ketoconazole does not have active metabolites of clinical importance; and (6) CYP3A inhibition is rapidly reversible when ketoconazole is discontinued.Warnings against the use of ketoconazole based on an alleged risk of liver injury, issued by the Food and Drug Administration (FDA) and the European Medicines Agency in 2013, are not supported by medical or scientific evidence.2-5 Specifically, there is no indication of substantive risk to healthy volunteers who receive ketoconazole as an index CYP3A inhibitor in DDI studies. Still, the regulatory warnings compel the clinical pharmacology and drug development communities to evaluate alternatives to ketoconazole. Proposed alternatives have included: ritonavir, cobicistat, itraconazole, posaconazole, and clarithromycin.2-7 A review of the available published evidence clearly indicates that ritonavir is the best choice as an alternative index inhibitor. Comparison of Ritonavir and Itraconazole Maximum InhibitionBoth ritonavir and itraconazole are strong CYP3A inhibitors in vitro, with ritonavir having greater inhibitory potency.8 Inhibition by ritonavir has both reversible and mechanism-based (time-dependent) components, [9][10][11] whereas inhibition by itraconazole is largely reversible. An earlier review evaluated clinical DDI studies in which oral midazolam was the index CYP3A substrate (victim), and the inhibitor was either ritonavir or itraconazole.5 The principal outcome variable was the ratio (R AUC ) of total area under the curve (AUC) for midazolam with inhibitor coadministration divided by AUC in the control condition. In 13 studies with ritonavir as inhibitor, the mean (AESE) R AUC was 14.5 AE 2.0, compared to 11.5 AE 1.2 in 15 studies of ketoconaz...

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

“…2,9,58 Ritonavir produces in vivo CYP3A inhibition similar to or greater than ketoconazole, and is the most appropriate perpetrator drug to serve as an alternative to ketoconazole in DDI studies of healthy volunteers. 2,63,64 Cobicistat is closely related to ritonavir, 65 and is another option to serve as an index CYP3A inhibitor. 61,63,64…”

“…2,63,64 Cobicistat is closely related to ritonavir, 65 and is another option to serve as an index CYP3A inhibitor. 61,63,64…”

Mechanisms and Consequences of Drug‐Drug Interactions

“…Ritonavir continues to be used as a boosting agent in HIV and HCV therapy. Ritonavir is the most potent of clinically available CYP3A inhibitors and also is a strong inhibitor of transport via P‐gp . Cobicistat is an alternative enhancer that was first approved in 2012 as part of a combination product, and approved as a single entity in 2014 .…”

“…Ritonavir is the most potent of clinically available CYP3A inhibitors and also is a strong inhibitor of transport via P-gp. [48][49][50] Cobicistat is an alternative enhancer that was first approved in 2012 as part of a combination product, and approved as a single entity in 2014. [51][52][53] Ritonavir and cobicistat are very similar in structure ( Figure 2) and similar or identical in pharmacologic properties and clinical efficacy as enhancing agents.…”

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 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).…”