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

  • Published on April 13, 2016
  • Drug Transporters
  • Enzyme Inhibition
  • Webinars

Presented by: Lydia Vermeer, Ph.D., Senior Scientist, Drug Transport

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.

Ketoconazole is a potent CYP3A4/5 inhibitor, and until recently, recommended by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a “strong” CYP3A4/5 inhibitor in clinical drug-drug interaction (DDI) studies. Ketoconazole sporadically causes liver injury or adrenal insufficiency. Because of this, the FDA and EMA recommended suspension of ketoconazole use in DDI studies in 2013. FDA specifically recommended use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors for use in clinical DDI studies, but many investigators have also used ritonavir as an alternative. Although the effects of these clinical CYP3A4/5 inhibitors on other CYPs are largely established, reports on the effects on the broad range of drug transporter activities are sparse. In this study, the inhibitory effects of ketoconazole, clarithromycin, ritonavir and itraconazole (and its CYP3A4-inhibitory metabolites, hydroxy-, keto- and N-desalkyl itraconazole) towards 13 drug transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3 and BSEP) were systematically assessed in transporter-expressing HEK-293 cell lines or membrane vesicles. In vitro findings were translated into clinical context with the basic static model approaches outlined by the FDA in their 2012 draft guidance on DDIs. The results indicate that, like ketoconazole, the alternative clinical CYP3A4/5 inhibitors ritonavir, clarithromycin and itraconazole each have unique transporter inhibition profiles. None of the alternatives to ketoconazole provided a clean inhibition profile towards the 13 drug transporters evaluated. The results provide guidance for the selection of clinical CYP3A4/5 inhibitors when transporters are potentially involved in a victim drug’s pharmacokinetics.


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Related Scientific Resources

Publication Review: “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

Scientific Poster: “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”


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