LAUSR

PURPOSE The objective of this study was to characterize the population pharmacokinetics of voriconazole and to identify factors that significantly affect pharmacokinetic parameters and to further investigate optimal dosage regimens in Chinese adult patients with hematologic malignancies. METHODS A prospective population pharmacokinetic analysis was performed on 186 concentration measurements obtained from 41 adult patients with hematologic malignancies. All enrolled patients were treated with voriconazole for diagnosed or suspected invasive fungal diseases. Oral voriconazole was routinely administered at a maintenance dose of 200 mg q12h. Serial blood samples were collected after steady-state of each patient. Monte Carlo simulation was applied to optimize dosage strategies. FINDINGS A one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.18 L/h, the volume of distribution was 88.9 L, and the absorption rate constant was 0.729 h-1. Clearance and steady-state exposure (AUC0-12) were found to be significantly associated with age and CYP2C19 phenotype. The average AUC0-12 of elderly patients (aged 60-90 years) was 2.1 times higher than that of relative younger patients (aged 18-59 years). The average AUC0-12 of poor metabolizers (PMs) was approximately 2.5 and 1.8 times higher than that of extensive and intermediate metabolizers (IMs), respectively. Considering both efficacy and tolerability, dosage regimens of 100 and 50 mg orally administered every 12 hours were recommended for elderly IMs and PMs, respectively. IMPLICATIONS A population pharmacokinetic model for voriconazole in Chinese adult patients with hematologic malignancies was successfully developed and could well capture voriconazole's pharmacokinetic characteristics. Age and CYP2C19 phenotype were found to significantly influence voriconazole clearance and should be taken into consideration clinically for dose optimization. The optimal dosage strategies in specific clinical scenarios were proposed in this study based on model simulation. Because of the high incidence of mutant CYP2C19*2 and *3 alleles, genetic testing seems to be necessary for Asian elderly patients when voriconazole treatment is initiated.