No Increased Risk of Ketoconazole Toxicity in Drug–Drug Interaction Studies

Abstract

In July 2013 the U.S. Food and Drug Administration (FDA) released a safety announcement regarding the use of ketoconazole and its adverse drug reactions. The FDA report advised against the use ketoconazole tablets as a first-line treatment for any fungal infections because of the risk of potentially serious drug-drug interactions and liver and adrenal gland complications. The European Medicines Agency (EMA) also proposed to limit the use of oral ketoconazole in fungal infections because of the same risk of harmful effects and interactions. In addition, the FDA also advised against the use of oral ketoconazole in drug interaction studies, in which it has been extensively used as an index inhibitor of drug metabolism. The aim of this investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity described by the FDA and EMA in published drug interaction studies with ketoconazole and compare these data with the toxicity reported for ketoconazole when used as antifungal treatment. In the drug interaction studies (2355 participants; healthy volunteers and patients; median treatment duration, 6 days), only 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In studies investigating ketoconazole treatment, patients were treated for 276 days (median), and 5.6% of patients had elevated liver enzyme activity. Because of the short treatment period in drug interaction studies the risk of drug-induced hepatic injury is considered very low. As such, we recommend that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers.

Proposal of a Safe and Effective Study Design for CYP3A‐Mediated Drug‐Drug Interactions

“…Published DDI studies in healthy volunteers using azoles as perpetrators are limited ( Figure 2) with the exception of ketoconazole, for which a large number of DDI studies exist due to the previous regulatory requirements of CYP3A inhibition studies. 2,8 The quality of safety reports on AEs in the literature is heterogeneous. The publications on the newer azoles (posaconazole and isavuconazole) report AEs in more detail than studies using the older drugs (itraconazole, voriconazole, and fluconazole).…”

“…Although ketoconazole used to be administered for 4 to 7 days before the victim drug, the frequency of AEs reported was very low regarding liver enzyme elevation. 2,8 Of the 29 publications with a cumulative itraconazole dose range of 100 to 4800 mg, one third did not report any side effects, and about 17% contained a clear statement that no AEs occurred at all (mostly studies with the lowest cumulative doses). About 43% contained incomplete, unspecific, or ambiguous AE descriptions or listings.…”

“…It was used in drug interaction studies of nearly all investigational new drugs during drug development, and a vast amount of knowledge of its inhibitory effects exists. 2 Because of safety concerns, the FDA now recommends the use of itraconazole, also classified as a strong inhibitor of CYP3A and P-gp. However, despite this recommendation, in clinical drug interaction trials, a different length of preexposure of itraconazole in comparison with ketoconazole has to be used to generate maximum inhibition, which has already been discussed in the literature.…”

Doravirine and the Potential for CYP3A-Mediated Drug-Drug Interactions

“…(iii) CYP3A inhibitor: ketoconazole. Ketoconazole is a strong CYP3A inhibitor (33) that also demonstrates autoinhibition after multiple doses (34) and, as such, is commonly used in DDI studies to probe the effect of CYP3A inhibition (35). Ketoconazole is an antifungal agent that can be used for treating opportunistic infections (34), which often occur in people living with HIV (36), although its current use is limited (37).…”

Ketoconazole and Liver Injury: A Five‐Year Update

“…Two studies, conducted independently and published at about the same time, evaluated ketoconazoleassociated liver injury in the context of healthy volunteer DDI pharmacokinetic studies. 2,12 Liver injury was defined based on biochemical criteria. The report of Banankhah et al 12 evaluated 53 DDI studies involving 971 subjects who were exposed to systemic ketoconazole.…”