The safety, toleration, and pharmacokinetics comparison of two
intravenous voriconazole formulations in healthy Chinese volunteers
after three ascending doses
Abstract
Objectives To evaluate the safety, toleration, and pharmacokinetics
(PKs) comparison of two intravenous voriconazole formulations after
three ascending dose administrations in healthy Chinese subjects.
Methods A randomized, double-blind, placebo- and positive-controlled
trial was conducted in three cohorts with a total of 42 healthy Chinese
subjects. Every cohort of 14 subjects was allocated in proportion
(8:4:2) to test formulation, positive voriconazole or placebo
successively by single first and then multiple dose administration of 3
mg/kg, 4 mg/kg, and 6 mg/kg. Key findings A total of 41 subjects
completed all drug administrations. The pharmacokinetics of test
formulations are characterized by high interindividual variability with
a coefficient of variance of Cmax up to 67.95% and AUC0-τ up to 70.16%
and nonlinear pharmacokinetics with a regression coefficient of Cmax of
1.31 and AUC0-τ of 1.75 in a single dose. In the steady state, RAuc
(mean±SD) of test drug vs positive control drug of 3 mg/kg, 4 mg/kg, and
6 mg/kg dose group was 5.18±1.07 and 5.26±0.99, 5.59±1.15 and 6.27±0.58,
and 5.82±0.47 and 5.52±0.76, respectively; and Rcmax (mean±SD) were
2.50±0.44 and 2.68±0.72, 2.63±0.46 and 3.11±0.57, and 2.79±0.28 and
2.55±0.34, respectively. Adverse events with 37 transient visual
disturbances were mainly mild. Conclusions The pharmacokinetics with
high interindividual variability, nonlinear characteristics and
significant dose-dependent accumulation were comparable in the two
formulations. The overall safety of the test formulation was tolerable.