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

• Published in: Clinical pharmacology and therapeutics 2009-12, Vol.86 (6), p.609-618
• Main Authors: Zhao, W, Elie, V, Roussey, G, Brochard, K, Niaudet, P, Leroy, V, Loirat, C, Cochat, P, Cloarec, S, André, J L, Garaix, F, Bensman, A, Fakhoury, M, Jacqz‐Aigrain, E
• Format: Article
• Language: English
• Subjects: Adolescent; Age Factors; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Body Weight; Child; Child, Preschool; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Drug Dosage Calculations; Drug Monitoring; Drug Therapy, Combination; Female; France; Hematocrit; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacokinetics; Kidney Transplantation; Male; Models, Biological; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Polymorphism, Genetic; Reproducibility of Results; Tacrolimus - administration & dosage; Tacrolimus - pharmacokinetics; Treatment Outcome
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2009.210

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