title: Limited Sampling Strategy for the Estimation of Tacrolimus Area Under the Concentration-Time Curve in Chinese Adult Liver Transplant Patients.
abstract: OBJECTIVE
  Limited sampling strategies (LSS) have been proposed as an alternative method for estimating area under concentration-time curve (AUC) of immunosuppressive agent tacrolimus (TAC). In this study, we aimed to develop the LSS models for predicting AUC of TAC in Chinese liver transplant patients.
  
  
  METHODS
  Twenty-eight adult liver transplant patients receiving immunosuppressive regimen including TAC were enrolled. A total of 47 pharmacokinetic profiles were obtained after 1 or 3 weeks therapy. TAC concentrations were determined before dose (0 h) and at 1, 1.5, 2, 2.5, 3, 4, 6, 8 and 12 h after dosing by LC-MS/MS assay. Optimal subset regression analysis was used to establish the models for estimating TAC AUC0-12. Prediction error (PE) and absolute PE were calculated. The agreement between predicted and measured AUC0-12 was investigated by Bland-Altman analysis. The obtained models were validated by bootstrap analysis. The prediction performance among various CYP3A5 and ABCB1 genotypes was compared. The models selected from previous published studies were also validated using our data.
  
  
  RESULTS
  Twenty-eight models including 1, 2, 3 and 4 blood time points sampling were established (r2 = 0.653-0.979). The best model for prediction of TAC AUC0-12 was 0.81 + 1.73C1 + 1.32C2 + 3.87C4 + 3.75C8 (r2 = 0.979). Forty profiles (85.1%) had estimated TAC AUC0-12 within ±15% of observed TAC AUC0-12. Model with C0-C2 (r2 = 0.880) can be used for outpatients who need monitoring to be carried out in a short period. We also found that ABCB1 genotype may be a reason of variation in the prediction performance. There was good correlation between predicted and measured AUC0-12 (r2 = 0.880-0.928) by using models from previous studies with sample collected within 4 h post dose.
  
  
  CONCLUSIONS
  The LSS is an effective approach for estimation of full TAC AUC0-12 in Chinese liver transplant patients.
authors.affiliation: Department of Pharmacy, Ruijin Hospital, Shanghai, PR China.
authors.forename: Xiao-Xue
authors.initials: XX
authors.lastname: Liu
authors.forename: Bei-Ming
authors.initials: BM
authors.lastname: Xu
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Song
authors.forename: Wan-Hua
authors.initials: WH
authors.lastname: Yang
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
mesh_terms: D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D005260:Female; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016031:Liver Transplantation / Q000009:adverse effects / Q000639:trends; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus