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No Increased Risk of Ketoconazole Toxicity in Drug-Drug Interaction Studies

Noémi Outeiro1, Nicolas Hohmann1, Gerd Mikus2

  • 1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.

Journal of Clinical Pharmacology
|July 14, 2016
PubMed

Insights

Ketoconazole poses risks for fungal infections but is safe for drug interaction studies. Liver injury risk is low in short-term drug interaction studies, unlike longer antifungal treatments.

Area of Science:

  • Pharmacology
  • Hepatotoxicity
  • Drug Metabolism

Background:

  • Regulatory agencies like the FDA and EMA have raised concerns about ketoconazole's safety.
  • Concerns include drug-drug interactions, liver, and adrenal gland complications with ketoconazole use.
  • Ketoconazole's use as an index inhibitor in drug interaction studies has been questioned due to safety concerns.

Purpose of the Study:

  • To evaluate ketoconazole-induced hepatotoxicity risks in drug interaction studies.
  • To compare these risks with toxicity data from ketoconazole's use as an antifungal treatment.
  • To determine if ketoconazole remains a safe CYP3A index inhibitor.

Main Methods:

  • Analysis of published drug interaction studies involving ketoconazole.
  • Comparison of adverse event data from drug interaction studies versus antifungal treatment studies.
  • Assessment of liver transaminase activity and reported deaths.

Main Results:

  • In drug interaction studies (2355 participants, median 6 days), 1.7% showed elevated liver enzymes, with no deaths.
  • In antifungal treatment studies (median 276 days), 5.6% of patients had elevated liver enzymes.
  • The risk of drug-induced hepatic injury is considered very low in short-term drug interaction studies.

Conclusions:

  • Ketoconazole demonstrates a very low risk of drug-induced hepatic injury in short-term drug interaction studies.
  • Ketoconazole can continue to be safely used as a CYP3A index inhibitor in drug interaction studies.
  • The safety profile of ketoconazole differs significantly between short-term drug interaction studies and long-term antifungal treatment.
Keywords:
CYP3A inhibitionadverse eventshepatic toxicityketoconazole

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