Population Pharmacokinetics and Pharmacogenetics of Tacrolimus in De Novo Pediatric Kidney Transplant Recipients

doi:doi:10.1038/clpt.2009.210

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Clinical Pharmacology & Therapeutics (2009) 86 6, 609–618. doi:10.1038/clpt.2009.210

Population Pharmacokinetics and Pharmacogenetics of Tacrolimus in De Novo Pediatric Kidney Transplant Recipients

W Zhao¹, V Elie¹, G Roussey², K Brochard³, P Niaudet⁴, V Leroy⁵, C Loirat⁵, P Cochat⁶, S Cloarec⁷, J L André⁸, F Garaix⁹, A Bensman¹⁰, M Fakhoury^1,11 and E Jacqz-Aigrain^1,11

¹Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France
²Department of Pediatric Nephrology, Hôpital Mère et Enfant, Nantes, France
³Department of Pediatric Nephrology, Hôpital des Enfants, Toulouse, France
⁴Department of Pediatric Nephrology, Hôpital Necker-Enfants Malades, Paris, France
⁵Department of Pediatric Nephrology, Hôpital Robert Debré, Paris, France
⁶Department of Pediatric Nephrology, Hôpital Femme Mère Enfant, Lyon, France
⁷Department of Pediatric Nephrology, CHRU, Tours, France
⁸Department of Pediatric Nephrology, Hôpital des Enfants, Nancy, France
⁹Department of Pediatric Nephrology, Hôpital de la Timone Enfants, Marseille, France
¹⁰Department of Pediatric Nephrology, Hôpital Trousseau, Paris, France
¹¹Clinical Investigation Center (CIC), INSERM 9202, Hôpital Robert Debré, Paris, France

Correspondence: E Jacqz-Aigrain, (evelyne.jacqz-aigrain@rdb.aphp.fr)

Received 29 March 2009; Accepted 26 August 2009; Published online 28 October 2009.

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Abstract

The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2–18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic–pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.