Population pharmacokinetics and covariate-based dosing individualization of voriconazole in lung transplant recipients.

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

Dosing Optimization of Posaconazole in Lung-Transplant Recipients Based on Population Pharmacokinetic Model.

Although posaconazole tablets show relatively low variability in pharmacokinetics (PK), the proportion of patients achieving the PK/PD target at the approved uniform dose for both prophylaxis and therapy is not satisfactory. The aim of this study was to develop a posaconazole population PK model in lung-transplant recipients and to propose a covariate-based dosing optimization for both prophylaxis and therapy. In this prospective study, 80 posaconazole concentrations obtained from 32 lung-transplant patients during therapeutic drug monitoring were analyzed using nonlinear mixed-effects modelling, and a Monte Carlo simulation was used to describe the theoretical distribution of posaconazole PK profiles at various dosing regimens. A one-compartment model with both linear absorption and elimination best fit the concentration-time data. The population apparent volume of distribution was 386.4 L, while an apparent clearance of 8.8 L/h decreased by 0.009 L/h with each year of the patient's age. Based on the covariate model, a dosing regimen of 200 mg/day for prophylaxis in patients ˃60 years, 300 mg/day for prophylaxis in patients ˂60 years and for therapy in patients ˃60 years, and 400 mg/day for therapy in patients ˂60 years has been proposed. At this dosing regimen, the PK/PD target for prophylaxis and therapy is reached in 95% and 90% of population, respectively, representing significantly improved outcomes in comparison with the uniform dose.