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A randomized, placebo-controlled (with respect to voriconazole), 2-period, multiple-dose intragroup fixed-dose sequence study was conducted in 34 healthy male subjects to evaluate the interactions between voriconazole (triazole antifungal agent) and efavirenz (reverse transcriptase inhibitor). In period 1, subjects received 200 mg twice-daily (bid) voriconazole (n = 17) or placebo (n = 17) for 3 days (400-mg bid loading doses on day 1). In period 2, following a 7-day washout, subjects received 400 mg once-daily (qd) efavirenz alone for 10 days (days 11-20). Then efavirenz was coadministered with 200 mg bid voriconazole or placebo for the next 9 days (days 21-29). Serial plasma voriconazole and efavirenz concentrations were measured on days 3, 19, and 29, and the safety data were collected throughout the study. The 400-mg qd efavirenz dose substantially reduced the steady-state mean voriconazole area under the curve over the dosing interval (AUC0-12) by 80% (90% confidence interval [CI], 75%-84%) and peak concentration (Cmax) by 66% (90% CI, 57%-73%). The decrease in voriconazole exposure during coadministration is probably mainly due to the induction of CYP2C19 and CYP2C9 by efavirenz. The 200 mg bid voriconazole increased the steady-state mean AUC0-24 and Cmax of efavirenz by 43% (90% CI, 36%-51%) and 37% (90% CI, 29%-46%), respectively. The increase in efavirenz exposure during coadministration is probably due to the inhibition of CYP3A4 by voriconazole. Coadministration of 200 mg bid voriconazole with 400 mg (or higher) qd efavirenz is contraindicated due to the clinically significant effect of efavirenz on voriconazole pharmacokinetics.

Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)], -82%; maximum concentration [C(max)], -66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC(0-12), -39%; C(max), -24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC(0-12), -14%; C(max), -24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.

In this report we compare the activity of two new antifungal agents, voriconazole (UK-109,496) and LY303366 with the activities of other antifungals including fluconazole, itraconazole, 5-fluorocytosine (5FC) and amphotericin B against 219 oral Candida spp. isolates from HIV-infected patients. We used the broth microdilution method following the guidelines of the NCCLS. The in-vitro activity of voriconazole (UK-109,496) (MIC(90) 0.12 mg/L) and LY303366 (CMI(90) 0.25 mg/L) against clinical isolates of Candida spp. was excellent and comparable with that of amphotericin B (MIC(90) 0.5 mg/L), and better than those of fluconazole (MIC(90) > or = 64 mg/L), itraconazole (MIC(90) 4 mg/L) and 5FC (MIC(90) 1 mg/L).