title: The Effect of Weight and CYP3A5 Genotype on the Population Pharmacokinetics of Tacrolimus in Stable Paediatric Renal Transplant Recipients.
abstract: 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.
authors.affiliation: Paediatric Nephrology Department, University Hospital Ghent, De Pintelaan 185, 9000, Ghent, Belgium. Agnieszka.Prytula@uzgent.be.|Paediatric Nephrology Department, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands. Agnieszka.Prytula@uzgent.be.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Prytuła
authors.affiliation: Paediatric Nephrology Department, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Karlien
authors.initials: K
authors.lastname: Cransberg
authors.affiliation: Paediatric Nephrology Department, Emma Children's Hospital, Amsterdam, The Netherlands.
authors.forename: Antonia H M
authors.initials: AH
authors.lastname: Bouts
authors.affiliation: Department of Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: Paediatric Nephrology Department, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: de Jong
authors.affiliation: Intensive Care and Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
authors.affiliation: Department of Hospital Pharmacy-Clinical Pharmacology Unit, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D019540:Area Under Curve; D001835:Body Weight / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D066027:Transplant Recipients
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus