Evaluation of Ketoconazole and its Alternative Clinical CYP3A4/5 Drug Transport Inhibitors

Evaluation of Ketoconazole and its Alternative Clinical CYP3A4/5 Drug Transport Inhibitors

Published:  5/29/2016 1:10:46 PM

Updated: 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

Ketoconazole is an orally available, synthetic, broad spectrum, antifungal agent. Approved in 1982 by the FDA for use in fungal infections, it is a known substrate and strong inhibitor of cytochrome P450 (CYP) 3A4 and 3A5.

Previously, a high dose of ketoconazole was considered the gold standard for use in clinical drug-drug interaction (DDI) as a strong CYP3A4/5 inhibitor. By 2013, ketoconazole use in clinical studies had been banned due in part to evidence demonstrating the potential for liver injury following long dosing periods. Typically, patients would exhibit asymptomatic, reversible liver function test abnormalities. As early as 1984, Van Tyle demonstrated evidence of DILI in approximately 0.1 to 1.0% of patients, with results indicating that there was no association with the dose, but with the duration of dosing. In later estimates, studies showed that ~134 per 100,00 persons, 4.9 cases per 10,000 patients, and 3.6 to 4.2% demonstrated liver abnormalities.

After ketoconazole was banned in clinical study use, the FDA recommended clarithromycin or itraconazole as an alternative, but indicating that other drugs may be used. Ritonavir was suggested by some as an alternative CYP3A4/5 inhibitor. Following an extensive study by Ke et al. where inhibitors were systematically evaluated, only itraconazole and clarithromycin were considered acceptable. Exclusion criteria included, the drug not being approved in the U.S., known non-specific inhibition of CYPs, safety issues, exclusive use with ritonavir, or only moderate information of CYP3A4/5.

There is minimal drug transporter data in the literature; which includes ketoconazole and ritonavir inhibition of P-gp and OATP1B1. The goal of this study was to allow for a more informed choice of a strong CYP3A4/5 inhibitor for clinical DDI studies involving a drug candidate known to be a substrate of one or more of the transporters and to help reduce confounding DDI results.

Published paper and webinar also available.

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