The ketoconazole legacy

It began innocently enough. Ketoconazole was marketed worldwide in 1981 for the systemic treatment of a variety of fungal infections. It was clearly an improvement over previously available therapies, such as amphotericin B, with respect to tolerability and adverse effects. However, ketoconazole hepatotoxicity was recognized as early as 1980,1 and was further described as a potential risk of ketoconazole treatment in case series and review articles.2-5 The manufacturer maintained that the incidence of ketoconazole-associated liver toxicity was very low.6 Based on early experimental studies, ketoconazole was also recognized as an inhibitor of microsomal drug oxidation.4, 7 Inhibition of cyclosporine clearance and elevation of plasma levels in humans was first reported in 1982,8, 9 and the deliberate use of ketoconazole as a cyclosporine “sparing” technique was described later in that decade.10 However clinical drug interactions of ketoconazole with other substrate drugs—such as antipyrine, caffeine, theophylline, and chlordiazepoxide—were small or negligible.7, 11-15 In retrospect, those negative drug interaction findings were probably attributable to the victim drugs being substrates for enzymes other than CYP3A. In the early 1990s, everything hit the fan on the scientific, regulatory, and political drug interaction scene. The trigger event was the terfenadine affair,16-18 along with the recognition of the CYP3A subfamily of the Cytochromes P450,19 the dual hepatic and enteric localization of CYP3A, and the extensive inhibition of CYP3A metabolic activity in humans due to usual clinical doses of ketoconazole.20 For orally-administered substrate drugs such as terfenadine, triazolam, and midazolam—that ordinarily undergo extensive presystemic extraction by CYP3A—coadministration of ketoconazole can produce huge increases in systemic exposure.17, 20-26 The terfenadine affair had a wide impact in terms of regulatory response, as well as the role of drug interaction science in the process of drug development. In the post-terfenadine era, ketoconazole was no longer just an antifungal drug—it became the cornerstone for academic and industrial research on the role of CYP3A in drug metabolism and disposition.20, 27-30 Ketoconazole was the prototype reversible and relatively selective inhibitor of human CYP3A isoforms for in vitro studies.20, 27-32 To determine the quantitative role of CYP3A in the clearance of a candidate substrate drug—and to document the “worst-case” scenario for CYP3A inhibition—the clinical ketoconazole drug-drug interaction study became the scientific standard. Hundreds of such studies have been done since the early 1990s. Nonetheless, ketoconazole-associated hepatotoxicity did not go away. Clinical reports and epidemiologic studies through to the present documented an increased risk of hepatic toxicity associated with ketoconazole use.33-37 The extent to which the risk is related to dose or duration of exposure is not clearly established. In any case, the FDA issued a Drug Safety Communication on July 26, 2013, stating that oral ketoconazole “can cause liver injury, which may potentially result in liver transplantation or death.” They further directed that oral ketoconazole “should not be a first-line treatment for any fungal infection.” In typical Phase 1 ketoconazole drug interaction studies, the duration of exposure to ketoconazole is limited, and study participants are healthy volunteers without liver disease or other predisposing factors. Whether the use of ketoconazole in this context carries measurable risk is unknown, and we know of no data on the prevalence of adverse hepatic effects in such studies. Still, the grim regulatory decree has probably brought the era of the Phase 1 ketoconazole drug interaction study to a close. IRBs and pharmaceutical sponsors will be unlikely to tolerate the perceived risk and liability. Availability of the drug for clinical use may become limited. While ketoconazole can still be used as an in vitro inhibitor, clinical investigators will need to come up with some other CYP3A inhibitor (such as ritonavir or itraconazole) to create the equivalent of the “CYP3A poor metabolizer.” Ketoconazole has an important legacy. Through this compound we have learned a great deal about drug metabolism and disposition. — David J. Greenblatt, MD, Editor-in-Chief Tufts University School of Medicine Boston, Massachusetts, 02111 (e-mail: [email protected])