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

  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},
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
Ketoconazole and Liver Injury: A Five‐Year Update
The current state of scientific knowledge on the topic of liver injury associated with ketoconazole and other azole antifungal agents is updated. Expand
Proposal of a Safe and Effective Study Design for CYP3A‐Mediated Drug‐Drug Interactions
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No Increased Risk of Ketoconazole Toxicity in Drug–Drug Interaction Studies
It is recommended that ketoconazole remain a safe CYP3A index inhibitor for use in drug interaction studies with healthy volunteers and the risk of drug‐induced hepatic injury is considered very low. Expand
The Effect of CYP3A Induction and Inhibition on the Pharmacokinetics of Laquinimod, a Novel Neuroimmunomodulator
Interaction assessments were conducted in healthy volunteers using single‐dose administration of laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazoles, fluconazole, and cimetidine) and rifampin to indicate that coadministration of laquimod with moderate to strong inhibitors of CYp3A or strong inducers of CYF3A may give rise to significant pharmacokinetic drug interactions. Expand
Ketoconazole - p-aminobenzoic acid cocrystal: revival of an old drug by crystal engineering.
The enhanced solubility and oral bioavailability of the cocrystal over Ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity indicate its potential use as an alternative antIFungal agent to the parent drug. Expand
Daily sesame oil supplementation mitigates ketoconazole-induced oxidative stress-mediated apoptosis and hepatic injury.
Sesame oil may be used as a nutritional supplement with existing antifungal therapies to neutralize the adverse hepatotoxic nature of antIFungal drugs by attenuating hepatic apoptosis through redox system to protect and heal liver injury in KCZ-treated mice. Expand
Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME–Tox and molecular docking studies of a series of imidazole derivatives
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Hepatocurative and Gluco-stabilizing Potentials of Ethanol Extract of Stem bark of Flacourtia indica in Aluminium Chloride induced Toxicity in Albino Wistar rats
The liver, a reddish – brown heaviest and largest internal organ weighs about 1.5 – 1.6 kg in an adult male and is about the size of an American football [1]. It is located behind the ribcage on theExpand


Liver injury associated with ketoconazole: Review of the published evidence
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
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
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
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
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
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.
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
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.
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
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