A population pharmacokinetic analysis of voriconazole according to CYP2C19 phenotype in healthy subjects
Yun Kim, Su-jin Rhee, Kyung-Sang Yu, In-Jin Jang, Seung Hwan Lee
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
Objectives: Voriconazole is a broad-spectrum antifungal agent for the treatment of invasive aspergillosis. The aims of this study were to develop a population pharmacokinetic model of voriconazole, and to evaluate the demographic and genomic determinants of plasma voriconazole levels.
Methods: A population pharmacokinetic analysis was performed using 1408 voriconazole concentrations in 82 healthy male subjects who received intravenous (IV) and/or oral voriconazole. The First-Order Conditional Estimation with Interaction estimation method was used with NONMEM (version 7.3). The effects of age, weight, height, and CYP2C19 phenotype on the pharmacokinetics of voriconazole were evaluated.
Results: A two-compartment model with first-order absorption and nonlinear (Michaelis-Menten) elimination with proportional residual error adequately described the time-concentration profiles of voriconazole. The typical values (inter-individual variability in CV%) of the maximum elimination rate (Vmax), Michaelis-Menten constant (Km), central volume of distribution (V2), peripheral volume of distribution (V3), inter-compartmental clearance (Q), and first-order absorption rate constant (ka) were 15.1 mg/h (24.7%), 0.115 mg/L (48.1%), 51.0 L (36.5%), 232 L (25.1%), 38.4 L/h (15.1%), and 1.09 /h (57.2%), respectively. Weight was found to be a significant covariate for the Q and V3 of voriconazole, while CYP2C19 phenotype had a significant effect on the Km. The Km estimates in CYP2C19 intermediate and poor metabolizers increased 1.4 and 5.46 fold over that in extensive metabolizers.
Conclusions: The pharmacokinetic parameters of IV and oral voriconazole were well described by the developed population model. The contribution of CYP2C19 to the pharmacokinetic variability of voriconazole in the patient population should be further investigated in the context of individualized optimal dosing to improve clinical outcome.