Population Pharmacokinetics of Voriconazole and Dose Optimization in
Chinese Elderly Patients
Abstract
Objectives: This study aimed to establish a population pharmacokinetic
model for elderly individuals receiving intravenous voriconazole, and to
assess and optimize the dosing regimens using a simulating approach.
Methods: A population pharmacokinetic analysis was conducted using the
NONMEN software based on 438 plasma concentrations from 150 elderly
patients receiving multiple intravenous doses of voriconazole. The
individualized optimal dosage regimen was proposed based on the obtained
population pharmacokinetics parameters. The final model was assessed by
the goodness of fit plots, non-parametric bootstrap method, and visual
predictive check. Monte Carlo simulations were carried out to assess and
optimize the dosing regimens with a therapeutic range of 2.0-5.0 mg/L as
the target plasma trough concentration (Cmin). Results: A
one-compartment model with first-order absorption and elimination fitted
well to the concentration-time profile of voriconazole. The typical
voriconazole clearance was 3.55 L/h, and the typical volume of
distribution was 194 L. Covariate analysis indicated that the CL of
voriconazole was substantially influenced by albumin (ALB), gamma
glutamyl transpeptidase, and direct bilirubin, while the volume was
associated with body weight. Conclusions: The first study on the
population pharmacokinetics of voriconazole in Chinese elderly people
was performed. Individualized dosing regimens were recommended for
different ALB levels based on population PK model prediction. The
proposed dosing regimens could provide a rationale for dosage
individualization to improve clinical outcomes and minimize drug-related
toxicities.