Voriconazole potentiates warfarin-induced prothrombin time prolongation.
OBJECTIVE
Voriconazole is a novel triazole with broad-spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voriconazole on the pharmacodynamics of warfarin by measuring prothrombin time, and also evaluated the safety and tolerability of the coadministered drugs.


METHODS
This was a double-blind, placebo-controlled, two-way crossover study in which healthy male subjects received either 300 mg voriconazole or placebo twice daily on days 1-12, plus a single oral dose of 30 mg warfarin on day 7 of each study period. Volunteers were randomized to one of the following treatment sequences: voriconazole + warfarin followed by placebo + warfarin or placebo + warfarin followed by voriconazole + warfarin. There was a washout of at least of 7 days between treatment periods.


RESULTS
The mean Cmax, AUCtau and tmax for voriconazole were 3736 ng ml-1, 25 733 ng.h ml-1, and 1.66 h, respectively. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve (AUEC) for prothrombin time during coadministration with voriconazole (17 s and 3211 s.h, respectively) were statistically significantly greater than the mean values observed during the placebo period (8 s and 2282 s.h ). Prothrombin times were still increased by a mean value of 5.4 s 144 h post warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 s in the placebo treatment period.


CONCLUSIONS
Coadministration of voriconazole and warfarin potentiates warfarin-induced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.
Purkins
Lynn
L
Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK.
Wood
Nolan
N
Kleinermans
Diane
D
Nichols
Don
D
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D004357:Drug Synergism; D006801:Humans; D008297:Male; D011517:Prothrombin Time; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D065819:Voriconazole; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D000925:Anticoagulants; D000935:Antifungal Agents; D004338:Drug Combinations; D011743:Pyrimidines; D014230:Triazoles; D014859:Warfarin; D065819:Voriconazole