TY - JOUR
T1 - The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients
AU - Prytuła, Agnieszka A.
AU - Cransberg, Karlien
AU - Bouts, Antonia H. M.
AU - van Schaik, Ron H. N.
AU - de Jong, Huib
AU - de Wildt, Saskia N.
AU - Mathôt, Ron A. A.
PY - 2016
Y1 - 2016
N2 - 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. 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
AB - 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. 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
U2 - https://doi.org/10.1007/s40262-016-0390-7
DO - https://doi.org/10.1007/s40262-016-0390-7
M3 - Article
C2 - 27138785
SN - 0312-5963
VL - 55
SP - 1129
EP - 1143
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 9
ER -