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Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam
Author(s) -
Saari Teijo I.,
Laine Kari,
Leino Kari,
Valtonen Mika,
Neuvonen Pertti J.,
Olkkola Klaus T.
Publication year - 2006
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 - 10.1016/j.clpt.2005.12.305
Subject(s) - midazolam , voriconazole , pharmacokinetics , medicine , pharmacodynamics , bioavailability , pharmacology , anesthesia , crossover study , oral administration , sedation , antifungal , alternative medicine , pathology , dermatology , placebo
Objective Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. Methods We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, α‐hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. Results Voriconazole reduced the clearance of intravenous midazolam by 72% ( P < .001) and increased its elimination half‐life from 2.8 to 8.3 hours ( P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration–time curve of oral midazolam by 3.8‐ and 10.3‐fold, respectively ( P < .001). The bioavailability of oral midazolam was increased from 31% to 84% ( P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam ( P < .001) but only weakly increased the effects of intravenous midazolam. Conclusion When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used. Clinical Pharmacology & Therapeutics (2006) 79 , 362–370; doi: 10.1016/j.clpt.2005.12.305