Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Liver Cirrhosis Patients.

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.