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30.04.2016 | Original Research Article | Ausgabe 9/2016

Clinical Pharmacokinetics 9/2016

The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients

Clinical Pharmacokinetics > Ausgabe 9/2016
Agnieszka A. Prytuła, Karlien Cransberg, Antonia H. M. Bouts, Ron H. N. van Schaik, Huib de Jong, Saskia N. de Wildt, Ron A. A. Mathôt



The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1 year after renal transplantation and simulate individualised dosage regimens.

Patients and methods

We included 54 children with median age of 11.1 years (range 3.8–18.4 years) with 120 pharmacokinetic profiles performed over 2 to 4 h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM®). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C→T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated.


A two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (P < 0.05) and γ-glutamyl transpeptidase (γGT) (P < 0.001) and was increased by 45 % in carriers of the CYP3A5*1 allele (P < 0.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2 mg/kg generates a pre-dose concentration (C 0) ranging from 5 to 10 µg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration–time curve (AUC) corresponding with a tacrolimus C 0 of 4–8 µg/L was 97 h·µg/L (interquartile range 80–120).


In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.

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