Population pharmacokinetics study of voriconazole and dosing regimen optimization in patients with invasive fungus infections / 中国药学杂志

ABSTRACT

OBJECTIVE: To characterize the pharmacokinetics of voriconazole, find the factors influencing pharmacokinetics and optimize dosing regimen in patients with invasive fungus infections(IFIs). METHODS: To prospectively quantitate the relationship between VRC parameters and covariates, a population pharmacokinetics analysis was conducted on pooled data from patients with invasive fungus infections. The list of covariates tested included demographic factors, biochemistry, concomitant medications and CYP2C19 genotype. The final model was internally evaluated using bootstrap method. Monte Carlo simulation was used to evaluate the effective of currently recommended dosing regimen and to design an optimized pharmacodynamics dosing strategy for VRC. RESULTS: Four hundred and six samples from 151 patients were collected for population pharmacokinetics analysis. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately fitted the data. VRC clearance was 6.95 L·h-1, volume of distribution was 200 L. The clearance was significantly association with age, alkaline phosphatase and CYP2C19 genotype. Bootstrap method confirmed that the pharmacokinetics parameters was accurate and the final model was robust. Monte Carlo simulation suggests that recommended dosing regimen for treat Aspegllius infections and 300 mg q12 h po or 200 mg q12 h iv. drip for treat Candida infections are effective. CONCLUSION: This study is able to show that the optimal VRC dosage regimens are successfully determined using prospective population pharmacokinetics analysis and Monte Carlo simulation.