title: Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients.
abstract: OBJECTIVE
  To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.
  
  
  METHODS
  The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates.
  
  
  RESULTS
  The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)(0.75) x EXP(-0.00158 x TPT) x EXP(0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l  h(-1)  kg(-1) (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%.
  
  
  CONCLUSIONS
  Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance.
authors.affiliation: Clinical and Practice Research Group, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast, UK.
authors.forename: Mariam H Abdel
authors.initials: MH
authors.lastname: Jalil
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Hawwa
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McKiernan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shields
authors.forename: James C
authors.initials: JC
authors.lastname: McElnay
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007223:Infant; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics; D016031:Liver Transplantation; D008297:Male; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D066027:Transplant Recipients
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: gene polymorphisms; liver transplant; nonmem; paediatrics; population pharmacokinetics; tacrolimus