Pharmacokinetics and Safety of Two Voriconazole Formulations after Intravenous Infusion in Two Doses in Healthy Chinese subjects

Abstract

Abstract Background Voriconazole, a second-generation triazole exhibits broad-spectrum antifungal activity. It is used for theprophylaxis and treatment of invasive fungal infections. The aim of this study was to assess the pharmacokinetic equivalence of a test formulation and reference formulation (Vfend®) of Voriconazole. Materials and Methods This was a randomized, open-label, single-dose, two-treatment, two-sequence, two-period, crossover phase I trial with 7-day washout periods. 48 subjects were divided into 4mg/kg and 6mg/kg groups equally.In each group, the subjects randomly received the test or reference formulations at the rate of 1:1. Following a 7-day washout period, the alternative formulations were received. The blood samples were collected at 0.5, 1.0, 1.33,1.42,1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 hours later in the 4 mg/kg group, while at 0.5, 1.0, 1.5, 1.75, 2.0, 2.08, 2.17, 2.33, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 hours later in the6 mg/kg group. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of Voriconazole. Safety was evaluated. Results The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0 − t, and AUC0−∞ in both 4 mg/kg and 6 mg/kg groups were within the prespecified bioequivalence limits between 80 ~ 125%. Inthe4mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (2552.4858 ± 447.5427) ng/mL, AUC0 − t was (11874.7937 ± 7156.5403) h*ng/mL and AUC0−∞ was (12834.9910 ± 9812.5167) h*ng/mL after a single dose of 4 mg/kg test formulation. The mean Cmax was (2615.3630 ± 464.3496) ng/mL, AUC0 − t was (12499.8864 ± 7256.9641) h*ng/mL and AUC0−∞ was (13415.6530 ± 9484.8426) h*ng/mL after a single dose of 4 mg/kg reference formulation. In the 6 mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (3537.6908 ± 691.3528) ng/mL, AUC0 − t was (24975.7418 ± 12363.8967) h*ng/mL and AUC0−∞ was (26212.2269 ± 14056.5960) h*ng/mL after a single dose of 6 mg/kg test formulation. The mean Cmax was (3504.0527 ± 667.4605) ng/mL AUC0 − t was (24989.6939 ± 12454.6114) h*ng/mL and AUC0−∞ was (26160.2473 ± 13995.9717) h*ng/mL after a single dose of 6 mg/kg reference formulation. Serious adverse event (SAE) was not observed. Conclusion In both 4 mg/kg group and 6 mg/kg group, equivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence for both test and reference formulations of Voriconazole.