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

Abstract

Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.

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

“…In the recently published analysis of drug interaction studies between 2005 and 2015, 53 studies involving 971 participants exposed to systemic ketoconazole revealed evidence of ketoconazoleassociated hepatic injury in 0.41% of participants. 11 In the studies in which patients were treated with ketoconazole for a longer period compared with the drug interaction studies, 8.7% showed elevated liver function tests. However, median treatment duration was 276 days.…”

“…In the drug interaction studies involving 2355 participants (healthy volunteers and patients), 40 participants were reported to have increased liver transaminase activity (1.7%), and no deaths were reported or associated with ketoconazole. In the recently published analysis of drug interaction studies between 2005 and 2015, 53 studies involving 971 participants exposed to systemic ketoconazole revealed evidence of ketoconazole‐associated hepatic injury in 0.41% of participants . In the studies in which patients were treated with ketoconazole for a longer period compared with the drug interaction studies, 8.7% showed elevated liver function tests.…”

“…Moreover, by the end of 2013 the FDA also recommended against the use of ketoconazole in drug–drug interaction studies, although in the current draft guideline on “Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations,” the use of ketoconazole as an inhibitor of CYP3A is still recommended. A recently published analysis of 53 drug–drug interaction (DDI) studies (2005–2015) including 971 healthy volunteers with systemic ketoconazole exposure reported no enhanced risk of ketoconazole‐related toxicity . Furthermore, there is an ongoing discussion concerning the optimal alternative to replace ketoconazole as an index inhibitor for CYP3A‐mediated metabolism for use in DDI studies …”

“…A recently published analysis of 53 drug-drug interaction (DDI) studies (2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) including 971 healthy volunteers with systemic ketoconazole exposure reported no enhanced risk of ketoconazole-related toxicity. 11 Furthermore, there is an ongoing discussion concerning the optimal alternative to replace ketoconazole as an index inhibitor for CYP3A-mediated metabolism for use in DDI studies. 12,13 The aim of the present investigation was to evaluate the risks of ketoconazole-induced hepatotoxicity as identified by the FDA and EMA in 2013 in all published DDI studies conducted using ketoconazole and compare these data with the incidence of toxicity reported during antifungal ketoconazole treatment.…”

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.…”