The ketoconazole legacy

Greenblatt, David J.

doi:10.1002/cpdd.100

Cited by 17 publications

(32 citation statements)

References 38 publications

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“…Ketoconazole produces rapid and reversible CYP3A inhibition, and DDI studies with ketoconazole preexposure durations as short as 1‐2 days produce maximal inhibition of CYP3A metabolic activity . In the present analysis, subjects who experienced probable or possible ketoconazole‐associated abnormalities (A, D, E, and F) had been exposed to ketoconazole for longer than the median study length of 1 week (13, 17, 9, and 9 days, respectively) prior to discontinuation of ketoconazole treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The azole antifungal agent ketoconazole is a potent inhibitor of human CYP3A isoforms, and is commonly used as an index CYP3A inhibitor in drug‐drug interaction (DDI) studies involving healthy volunteers . On July 26, 2013, the United States Food and Drug Administration (FDA) and the European Medical Agency (EMA) released directives imposing limitations on the use of oral ketoconazole as a first‐line antifungal treatment, citing a potential risk for acute hepatic injury as the primary concern, along with a risk of adrenal insufficiency and drug interactions .…”

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confidence: 99%

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

Banankhah

Garnick

Greenblatt

2016

The Journal of Clinical Pharma

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Banankhah

Garnick

Greenblatt

2016

The Journal of Clinical Pharma

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“…In addition to having antifungal properties, ketoconazole was also became recognized as a potent inhibitor of human drug metabolism (specifically via CYP3A isoforms), beginning with reports around 1982 describing inhibition of cyclosporine clearance . Ketoconazole also inhibits a number of CYP enzymes involved in steroidogenesis, leading to reports of adrenal insufficiency in some clinical situations .…”

Section: Overview Of Ketoconazolementioning

confidence: 99%

“…CYP3A inhibition by ketoconazole has assumed major importance in drug metabolism research and the drug development process . If a candidate drug is identified as a possible or probable substrate for biotransformation via CYP3A isoforms, a controlled ketoconazole drug interaction study can address critical clinical and safety issues.…”

Section: Metabolic Effects Of Ketoconazole: Drug‐drug Interactionsmentioning

confidence: 99%

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Liver injury associated with ketoconazole: Review of the published evidence

Greenblatt

2014

The Journal of Clinical Pharma

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The azole antifungal agent ketoconazole has been available since 1981 for the treatment of fungal infections. In 2013, the American Food and Drug Administration and the European Medicines Agency issued warnings or prohibitions against the clinical use of oral ketoconazole due to the risk of liver injury which may lead to liver transplantation or death. From the available published evidence it is difficult to determine the actual incidence or prevalence of liver injury during clinical use of ketoconazole as an antifungal. Hepatic injury, when it occurs, is generally evident as asymptomatic and reversible abnormalities of liver function tests. However, serious liver injury has been reported. Alternatives to ketoconazole (such as itraconazole, fluconazole, voriconazole, and terbinafine) are available, but improved safety with respect to liver injury risk is not clearly established. We are not aware of published reports of significant ketoconazole-associated liver injury in volunteer study participants when ketoconazole has been used as a CYP3A inhibitor in the context of clinical research on drug metabolism. Possible alternatives to ketoconazole as prototype CYP3A inhibitors include ritonavir and potentially itraconazole, but not clarithromycin.

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Antiretroviral boosting by cobicistat, a structural analog of ritonavir

Greenblatt

2014

Clinical Pharm in Drug Dev

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The ketoconazole legacy

Cited by 17 publications

References 38 publications

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

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

Liver injury associated with ketoconazole: Review of the published evidence

Antiretroviral boosting by cobicistat, a structural analog of ritonavir

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