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Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole
Author(s) -
Olkkola Klaus T,
Backman Janne T,
Neuvonen Pertti J
Publication year - 1994
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1994.60
Subject(s) - ketoconazole , itraconazole , midazolam , crossover study , placebo , pharmacology , pharmacokinetics , drug interaction , medicine , anesthesia , dermatology , antifungal , alternative medicine , pathology , sedation
Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double‐blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration‐time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test), the interaction was statistically significant (p < 0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by ketoconazole and itraconazole may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving ketoconazole and itraconazole should be avoided. Clinical Pharmacology and Therapeutics (1994) 55, 481–485; doi: 10.1038/clpt.1994.60