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

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Abstract

Background

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.

Results

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).

Conclusions

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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Authors and Affiliations

  1. Paediatric Nephrology Department, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium

    Agnieszka A. Prytuła

  2. Paediatric Nephrology Department, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Agnieszka A. Prytuła, Karlien Cransberg & Huib de Jong

  3. Paediatric Nephrology Department, Emma Children’s Hospital, Amsterdam, The Netherlands

    Antonia H. M. Bouts

  4. Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Saskia N. de Wildt

  5. Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands

    Ron H. N. van Schaik

  6. Department of Hospital Pharmacy-Clinical Pharmacology Unit, Academic Medical Center, Amsterdam, The Netherlands

    Ron A. A. Mathôt

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  1. Agnieszka A. Prytuła
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Correspondence to Agnieszka A. Prytuła.

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Agnieszka Prytuła has been supported by a Clinical Research Grant funded by the University of Ghent. Saskia de Wildt has been supported by a ZonMW Clinical Fellowship. Agnieszka Prytuła, Karlien Cransberg, Antonia Bouts, Ron van Schaik, Huib de Jong, Saskia de Wildt and Ron Mathôt have no conflicts of interest related to this work to declare.

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Prytuła, A.A., Cransberg, K., Bouts, A.H.M. et al. The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients. Clin Pharmacokinet 55, 1129–1143 (2016). https://doi.org/10.1007/s40262-016-0390-7

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