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

Abstract

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.

Keywords:

• Voriconazole
• antifungals
• lung transplantation
• therapeutic drug monitoring
• nonlinear mixed-effects modelling

Acknowledgment

The authors would like to thank Jan Simonek, MD, Jiri Vachtenheim, MD, Jiri Pozniak, MD, Monika Svorcova, MD, Jan Kolarik, MD, Rene Novysedlak, MD, for the medical care for the patients enrolled in the study.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval statement

The study was approved by Ethics Committee of Motol University Hospital under No. EK-873/22 on 11 August 2019 and was conducted in accordance with the Declaration of Helsinki.

Patient consent statement

Written informed consent was obtained from all subjects prior to their inclusion in the analysis.

Additional information

Funding

This study was supported by MH CZ-DRO (Motol University Hospital, Prague, Czech Republic 00064203) and by the Charles University project Cooperatio (research area PHAR).