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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\u2010associated 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\u2010associated 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.<\/jats:p>","DOI":"10.1002\/jcph.711","type":"journal-article","created":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T16:02:50Z","timestamp":1454342570000},"page":"1196-1202","source":"Crossref","is-referenced-by-count":17,"title":["Ketoconazole\u2010Associated Liver Injury in Drug\u2010Drug Interaction Studies in Healthy Volunteers"],"prefix":"10.1002","volume":"56","author":[{"given":"Peymaan S.","family":"Banankhah","sequence":"first","affiliation":[{"name":"Master of Science in Biomedical Sciences Program Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle A.","family":"Garnick","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Master of Science in Biomedical Sciences Program Tufts University School of Medicine  Boston Massachusetts USA"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,2,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200038020-00002"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.400"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.100"},{"key":"e_1_2_7_5_1","unstructured":"FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. UCM 362444: 26 July2013."},{"key":"e_1_2_7_6_1","unstructured":"European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. Benefit of oral ketoconazole does not outweigh risk of liver injury in fungal infections. EMA\/458028\/2013.2013."},{"key":"e_1_2_7_7_1","unstructured":"FDA advises against using oral ketoconazole in drug interaction studies due to serious potential side effects. UCM 371017.2013."},{"key":"e_1_2_7_8_1","unstructured":"Therapeutic Goods Administration.Oral ketoconazole (Nizoral) 200 mg tablets: product deregistration. Australian Government Department of Health.2013."},{"key":"e_1_2_7_9_1","unstructured":"CFDA issues announcement on cessation of production distribution and use of ketoconazole oral formulation. 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