Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration

Aims Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is all inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CY112C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered. Methods Two placebo-controlled parallel-group studies were conducted in healthy male volunteers. Study A was all open-label study and investigated the effect of phenytoin (300 mg once daily) on the steady-state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double-blind randomized study to investigate the effects of voriconazole (400 mg twice daily) oil the steady-state pharmacokinetics of phenytoin (300 mg once daily). C-max and AUC(tau) were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study 13). All adverse events were recorded. Results Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole C-max and AUC(tau) were 60.7% [90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% Cl 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole C-max and AUC(tau) were 134% (90% Cl 89.2, 200) and 139% (90% Cl 97.3, 199), respectively. Stud), B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin C-max 167% (90% Cl 144, 193) and phenytoin AUC(tau) 181% (90% Cl 156, 210). All treatments were well tolerated: most adverse events were mild/moderate mid transient. Conclusions Repeat dose administration of phenytoin decreased the mean steady-state C-max and AUC(tau) of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 ing b.d. voriconazole increased the mean steady-state C-max and AUC(tau) of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.