Population Pharmacokinetics of Voriconazole in Patients with Invasive Aspergillosis: Serum Albumin Level as a Novel Marker for Clearance and Dosage Optimization

Background:Voriconazole (VRCZ) is an antifungal triazole recommended as an effective first-line agent for treating invasive aspergillosis.Objectives:To develop a population pharmacokinetic model of VRCZ and trough concentration-based dosing simulation for dynamic patient conditions.Methods:The authors combined plasma VRCZ data from intensive sampling, and retrospective trough concentration monitoring for analysis. Nonlinear mixed-effects modeling with subsequent model validation was performed. The recommended dosage regimens were simulated based on the developed model.Results:The study participants included 106 patients taking oral VRCZ. A linear one-compartment model with first-order elimination and absorption best described the observed data. The CYP2C19 phenotypes did not influence the pharmacokinetic parameters. Serum albumin (SA) levels and gamma-glutamyl transferase significantly correlated with the VRCZ clearance rate, whereas the actual body weight influenced the volume. A visual predictive check showed good consistency with the observed data, whereas SA levels across the treatment course correlated with linear clearance, irrespective of the CYP2C19 phenotype. Patients with SA levels ≤30 g/L had lower linear clearance than that in patients with SA levels >30 g/L. Dosing simulation based on the developed model indicated that patients with SA levels of ≤30 g/L required a lower daily maintenance dose to attain the therapeutic trough level.Conclusions:SA level was identified as a novel marker associated with VRCZ clearance. This marker may be a practical choice for physicians to perform therapeutic drug monitoring and optimize VRCZ dosage.