title: Population pharmacokinetics of tacrolimus in Thai kidney transplant patients: comparison with similar data from other populations.
abstract: OBJECTIVE
  Tacrolimus, the most widely used calcineurin inhibitor in kidney transplantation, has a narrow therapeutic window with high interindividual variability in its pharmacokinetics. Clinically feasible models that combine important factors may help guide individual tacrolimus dosage adjustment in kidney transplant patients. The purpose of this study was to develop a population pharmacokinetic model and investigate the influence of clinical factors on the pharmacokinetics of tacrolimus in adult Thai kidney transplant patients from routine data monitoring.
  
  
  METHODS
  A total of 1183 whole blood concentrations from 96 patients were characterized using nonlinear mixed-effects modelling. Clinical factors tested for influence on pharmacokinetic parameters were weight, haemoglobin, duration of tacrolimus therapy, prednisolone dose, serum albumin and estimated glomerular filtration rate.
  
  
  CONCLUSIONS
  A one-compartment model with first-order absorption best described the data. The population estimate of tacrolimus apparent clearance (CL/F) and apparent volume of distribution (V/F) in the final population model was 21·5 L/h (95% CI; 18·38, 24·34) and 333 L (95% CI; 222·66, 484·35), respectively. CL/F increased with decreasing haemoglobin levels and decreased with increasing duration of tacrolimus therapy (both P < 0·001). The population pharmacokinetic equation that predicted CL/F of tacrolimus was CL/F = 21·5 × exp((-0·05 () (HB) ( - 11·8)))  × (DOT/125)(-0·06) , where CL/F was tacrolimus apparent oral clearance (L/h), HB was haemoglobin levels (g/dL), and DOT was duration of tacrolimus therapy (days). No covariates significantly influenced V/F.
  
  
  CONCLUSIONS
  The first population pharmacokinetic model of tacrolimus in Thai adult kidney transplant patients was developed and validated. Haemoglobin and duration of tacrolimus therapy could partly explain the interindividual variability in the apparent clearance of tacrolimus. This manuscript also provides a summary review of previously reported population pharmacokinetic models of twice daily tacrolimus in adult kidney transplant recipients.
authors.affiliation: Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Vadcharavivad
authors.affiliation: Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Praisuwan
authors.affiliation: Praram 9 Hospital, Bangkok, Thailand.
authors.forename: N
authors.initials: N
authors.lastname: Techawathanawanna
authors.affiliation: Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: W
authors.initials: W
authors.lastname: Treyaprasert
authors.affiliation: Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.|Excellence Center of Organ Transplantation, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
authors.forename: Y
authors.initials: Y
authors.lastname: Avihingsanon
mesh_terms: D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005919:Glomerular Filtration Rate; D006454:Hemoglobins; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011239:Prednisolone / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013785:Thailand; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D011239:Prednisolone; D016559:Tacrolimus
keywords: Nonlinear Mixed Effect Model; kidney transplantation; population pharmacokinetics; tacrolimus; therapeutic drug monitoring