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.