Abstract
Background and Objectives
TacrolimusPR is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimusPR in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimusPR pharmacokinetics, including CYP3A5 polymorphism.
Methods
Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene.
Results
The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)0.75] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2 ± 10.1 vs. 53.5 ± 20.2 L/h, p = 0.01).
Conclusions
The population pharmacokinetic model of tacrolimusPR was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus PR dosing regimen in routine clinical practice.
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Acknowledgments
We thank all the children and their families participating in this study. We also acknowledge the local clinical investigators (Marc Fila, Sonia Azib, Theresa Kwon, Anne Laure Leclerc, Marie-Alice Macher, Ferielle Louillet and Daolun Zhang) for conducting the study and technicians (Christel Grondin, Michel Popon, Samira Benakouche and Yves Médard) for technical support. This work was supported by Global Research in Paediatrics – Network of Excellence (GRIP, EU-funded FP7 project, Grant Agreement number 261060).
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The authors declare no conflict of interest related to this work
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Zhao, W., Fakhoury, M., Baudouin, V. et al. Population pharmacokinetics and pharmacogenetics of once daily prolonged-release formulation of tacrolimus in pediatric and adolescent kidney transplant recipients. Eur J Clin Pharmacol 69, 189–195 (2013). https://doi.org/10.1007/s00228-012-1330-6
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DOI: https://doi.org/10.1007/s00228-012-1330-6