No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers

Abstract

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. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together.

Methods: Two randomized placebo-controlled studies were conducted in healthy male volunteers. Study A was an open parallel-group study of the effect of indinavir on the steady-state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1-7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8-17). Study B was a double-blind, randomized, two-way crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7-day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded.

Results: Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCtau were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCtau, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies.

Conclusions: The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.

Figure 1

Mean plasma concentrations of voriconazole in Study A (days 7 and 17).

Figure 2

Mean plasma concentrations of indinavir in Study B (day 7).