title: Population pharmacokinetics of tacrolimus in pediatric liver transplantation: early posttransplantation clearance.
abstract: BACKGROUND
  Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology.
  
  
  METHODS
  The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients.
  
  
  RESULTS
  An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h(-1)·kg(-0.75) immediately after transplantation, increasing to a maximum of 1.37 L·h(-1)·kg(-0.75). Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time.
  
  
  CONCLUSIONS
  A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
authors: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. wallinjo@lilly.com
authors: Johan E
authors: JE
authors: Wallin
authors: Martin
authors: M
authors: Bergstrand
authors: Henryk E
authors: HE
authors: Wilczek
authors: Per S
authors: PS
authors: Nydert
authors: Mats O
authors: MO
authors: Karlsson
authors: Christine E
authors: CE
authors: Staatz
mesh_terms: D000293:Adolescent; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D007408:Intestinal Absorption; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008499:Medical Records; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011184:Postoperative Period; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus