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Objectives The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). Methods To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. Results The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. Conclusions This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations. [ABSTRACT FROM PUBLISHER]

This study evaluated whether contemporary echinocandin regimens achieved pharmacokinetic/pharmacodynamic targets in ICU patients and general patient populations (GPPs) and assessed caspofungin (CAS) regimens in hepatic impairment (HI) patients. A Monte Carlo simulation was performed using previously published data. Recommended dosing regimens of echinocandins in ICU patients, GPPs and healthy volunteers were evaluated: 70 mg loading dose then 50 mg maintenance dose (70/50 mg) for CAS; 100 mg q24h for micafungin (MCF); and 200/100 mg for anidulafungin (ANF). Moreover, CAS 70 mg and 100 mg q24h in GPPs, and CAS 70/50 mg and 70/35 mg in mild and moderate HI patients, respectively, were evaluated. Cumulative fraction of response (CFR) was calculated for each dosing regimen. For Candida albicans , CFRs for the recommended doses of CAS, MCF and ANF were 95.8%, 13.5% and 50.5% in ICU patients and 96.3%, 42.4% and 61.6% in GPPs, respectively; for Candida glabrata , CFRs were 99.4%, 90.6% and 44.6% in ICU patients and 99.5%, 97.1% and 59.8% in GPPs. For Candida parapsilosis , CFRs of echinocandins for standard regimens were <70%; only CAS 100 mg q24h achieved the target CFR. CAS 70/50 mg and 70/35 mg in mild and moderate HI patients were appropriate. Considerable interindividual variability was observed. For C. albicans and C. glabrata , CAS is good choice both for ICU and other patient populations, but for C. parapsilosis an increased dose should be considered. For MCF and ANF, administering higher doses with longer dosing intervals achieves better target attainment and should be investigated in clinical trials. [ABSTRACT FROM AUTHOR]