The pharmacokinetics and safety of intravenous voriconazole - a novel wide-spectrum antifungal agent.

Aims: Voriconazole is a new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. These studies evaluated the pharmacokinetics and safety of intravenous voriconazole in healthy male volunteers.

Methods: Two single-blind, placebo-controlled studies were conducted. In Study A, 12 subjects were randomized to voriconazole (3 mg kg-1) or placebo, administered once daily on days 1 and 12, and every 12 h on days 3-11. In Study B, 18 subjects were randomized to voriconazole or placebo, with voriconazole being administered as a loading dose at 6 mg kg-1 twice on day 1, then at 3 mg kg-1 twice daily on days 2-9, and once at 3 mg kg-1 on day 10.

Results: In both studies, the plasma concentrations of voriconazole increased rapidly following the initiation of dosing. Minimum observed plasma concentration (Cmin) values at steady state were above the in vitro minimum inhibitory concentrations (MICs) for most fungal pathogens (Cmin > 0.8 micro g ml-1). The use of a loading dose in Study B resulted in a shorter time to steady-state Cmin values than was observed in Study A. Values of the final day plasma pharmacokinetic parameters in Studies A and B were similar: maximum observed plasma concentration (Cmax) 3621 and 3063 ng ml-1; areas under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) 16 535 and 13 245 ng.h ml-1, and terminal elimination phase half-lives (t1/2) 6.5 and 6.7 h, respectively. On multiple dosing, voriconazole accumulated (AUCtau accumulation ratio 2.53-3.17, Study A) at a level that was not predictable from single-dose data. The mean concentration-time profiles for voriconazole in saliva were similar to those in plasma. Multiple doses of voriconazole were well tolerated and no subject discontinued from either study. Seven cases of possibly drug-related visual disturbance were reported in three subjects (Study B).

Conclusions: Administration of a loading dose of 6 mg kg-1 i.v. voriconazole on the first day of treatment followed by 3 mg kg-1 i.v. twice daily achieves steady state by the third day of dosing. This dosage regimen results in plasma levels of the drug that rapidly exceed the minimum inhibitory concentrations (MICs) against important fungal pathogens, including Aspergillus spp.