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

@article{Banankhah2016KetoconazoleAssociatedLI,
  title={Ketoconazole‐Associated Liver Injury in Drug‐Drug Interaction Studies in Healthy Volunteers},
  author={Peymaan Banankhah and Kyle Garnick and David J Greenblatt},
  journal={The Journal of Clinical Pharmacology},
  year={2016},
  volume={56}
}
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… Expand
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References

SHOWING 1-10 OF 71 REFERENCES
Liver injury associated with ketoconazole: Review of the published evidence
TLDR
It is difficult to determine the actual incidence or prevalence of liver injury during clinical use of ketoconazole as an antifungal, but there are not aware of published reports of significant ketoconAZole‐associated liver injury in volunteer study participants when ketconazole has been used as a CYP3A inhibitor in the context of clinical research on drug metabolism. Expand
Evidence‐based choice of ritonavir as index CYP3A inhibitor in drug‐drug interaction studies
TLDR
A review of the available published evidence clearly indicates that ritonavir is the best choice as an alternative index inhibitor for CYP3A inhibitors. Expand
Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects
TLDR
Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo, andsafinamide can be administered together with potent CYP 3A4 inhibitors without any requirement for dose adjustment. Expand
Effect of Ketoconazole on the Pharmacokinetics of Maribavir in Healthy Adults
TLDR
The pharmacokinetic findings, in combination with the acceptable tolerability within the maribavir and marIBavir-plus-ketoconazole treatment groups, suggest that no dose adjustment of maribvir is necessary when coadministered with CYP3A4 inhibitors or substrates. Expand
Effects of the Antifungal Agents on Oxidative Drug Metabolism
TLDR
The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. Expand
Effects of Rifampin and Ketoconazole on the Pharmacokinetics of Nilotinib in Healthy Participants
TLDR
The results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible. Expand
Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies.
TLDR
Ritonavir produces CYP3A inhibition equivalent to or greater than ketoconazole, and is the best index CYP2A inhibitor alternative to ketoconavir, and can be considered for drug-drug interaction studies. Expand
Best practices for the use of itraconazole as a replacement for ketoconazole in drug–drug interaction studies
TLDR
In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the Use of itRaconazoles in such studies. Expand
Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status.
TLDR
Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L and severe acute liver injury and coagulopathy with hyperbilirubinemia and one patient developed acute liver failure due to ketoconazole. Expand
The ketoconazole legacy
  • D. Greenblatt
  • Medicine
  • Clinical pharmacology in drug development
  • 2014
TLDR
In the post-terfenadine era, ketoconazole was no longer just an antifungal drug—it became the cornerstone for academic and industrial research on the role of CYP3A in drug metabolism and disposition, and the clinical ketconazole drug-drug interaction study became the scientific standard. Expand
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5
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