title: 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.
authors.affiliation: Master of Science in Biomedical Sciences Program, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Peymaan S
authors.initials: PS
authors.lastname: Banankhah
authors.affiliation: Graduate Programs in Pharmacology and Drug Development and in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Garnick
authors.affiliation: Master of Science in Biomedical Sciences Program, Tufts University School of Medicine, Boston, Massachusetts, USA. DJ.Greenblatt@Tufts.edu.|Graduate Programs in Pharmacology and Drug Development and in Pharmacology and Experimental Therapeutics, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, Massachusetts, USA. DJ.Greenblatt@Tufts.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Greenblatt
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000935:Antifungal Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects*; D008111:Liver Function Tests
chemical_list: D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007654:Ketoconazole
keywords: CYP3A; drug-drug interaction studies; healthy volunteers; ketoconazole; liver injury