Voriconazole and fluconazole increase the exposure to oral diazepam.
OBJECTIVE
We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam.


METHODS
Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h.


RESULTS
In the voriconazole phase, the area under the plasma concentration time curve (AUC 0-infinity) of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t(1/2)) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the AUC 0-infinity of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t(1/2) was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly.


CONCLUSIONS
Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.
Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, 20520, Turku, Finland. teijo.saari@tyks.fi
Teijo I
TI
Saari
Kari
K
Laine
Leif
L
Bertilsson
Pertti J
PJ
Neuvonen
Klaus T
KT
Olkkola
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D015725:Fluconazole / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003708:Nordazepam / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole; D014851:Wakefulness / Q000187:drug effects
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; D014230:Triazoles; D003708:Nordazepam; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole; D003975:Diazepam