title: A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients.
abstract: OBJECTIVE
  To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication.
  
  
  METHODS
  A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, p.o.) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check.
  
  
  RESULTS
  A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus.
  
  
  CONCLUSIONS
  Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.
authors.affiliation: 1] General Hospital of Armed Police Forces, Beijing 100039, China [2] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [3] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Yan-xia
authors.initials: YX
authors.lastname: Lu
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Qing-hong
authors.initials: QH
authors.lastname: Su
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Ke-hua
authors.initials: KH
authors.lastname: Wu
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Yu-peng
authors.initials: YP
authors.lastname: Ren
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Tian-yan
authors.initials: TY
authors.lastname: Zhou
authors.affiliation: 1] Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China [2] State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014838:Volunteers; D055815:Young Adult
chemical_list: D016559:Tacrolimus