title: Factors affecting the apparent clearance of tacrolimus in Korean adult liver transplant recipients.
abstract: OBJECTIVE
  To identify the factors affecting tacrolimus apparent total body clearance (Cl/F [F = bioavailability]) in adult liver transplant recipients.
  
  
  METHODS
  Population pharmacokinetic analysis using data from a retrospective chart review.
  
  
  METHODS
  University-affiliated hospital in Seoul, South Korea.
  
  
  METHODS
  Fifty-one adult liver transplant recipients who had received tacrolimus after transplantation.
  
  
  RESULTS
  Data on 35 adult liver transplant recipients for model building and 16 patients for model validation were obtained retrospectively. Population average parameter estimates of Cl/F and apparent volume of distribution (V/F) were sought by using the nonlinear mixed-effect model (NONMEM) program. A number of clinical covariates were screened for their influence on these pharmacokinetic parameters. The final optimal population model related Cl/F to total bilirubin, early (< or = 3 days) and late (> 35 days) postoperative days, international normalized ratio (INR), and graft:recipient weight ratio (GRWR). The NONMEM estimates indicated that the Cl/F of tacrolimus was decreased in patients with a small graft, hyperbilirubinemia, and a high INR. In addition, the Cl/F of tacrolimus almost doubled 4 days after transplantation, but decreased with an increase in duration of therapy after day 35. Mean prediction error and mean absolute prediction error were 0.26 and 3.78 ng/ml, respectively, for the validation sample. A final analysis in all 51 patients, which consisted of 1775 blood samples for concentration measurements, identified the following regression model: Cl/F (L/hr) = (0.36 + 2.01/POD * L) * TBIL(-0.23 (TBIL = 1 if TBIL level < or = 1.2 mg/dl, otherwise TBIL = TBIL level)) *49((if POD < or = 3 days)) * 0.75((if INR > 1.4)) * 0.86((if GRWR < or = 1.25%)) * WT, where L was 1 if postoperative day (POD) was greater than 35 days, otherwise L was 0; V/F was 568 L, TBIL was total bilirubin, and WT was body weight. The interindividual variabilities (coefficients of variation) in Cl/F and V/F were 35.35% and 68.12%, respectively. The residual variability was 3.14 ng/ml.
  
  
  CONCLUSIONS
  These findings could be useful to the health care provider for adjustment of tacrolimus dosage in adult liver transplant recipients with various clinical factors.
authors.affiliation: Department of Pharmacy, Seoul National University Hospital, Jongno-gu, Seoul, South Korea.
authors.forename: Ju Yeun
authors.initials: JY
authors.lastname: Lee
authors.forename: Hyeon Joo
authors.initials: HJ
authors.lastname: Hahn
authors.forename: In Ja
authors.initials: IJ
authors.lastname: Son
authors.forename: Kyung Suk
authors.initials: KS
authors.lastname: Suh
authors.forename: Nam Joon
authors.initials: NJ
authors.lastname: Yi
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
authors.forename: Wan Gyoon
authors.initials: WG
authors.lastname: Shin
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D001663:Bilirubin / Q000097:blood; D001682:Biological Availability; D001835:Body Weight; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D019934:International Normalized Ratio; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008297:Male; D008499:Medical Records; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009929:Organ Size; D012044:Regression Analysis; D015203:Reproducibility of Results; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D001663:Bilirubin; D016559:Tacrolimus