title: Evaluation of limited sampling methods for estimation of tacrolimus exposure in adult kidney transplant recipients.
abstract: OBJECTIVE
  To examine the predictive performance of limited sampling methods for estimation of tacrolimus exposure in adult kidney transplant recipients.
  
  
  METHODS
  Twenty full tacrolimus area under the concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) profiles (AUCf) were collected from 20 subjects. Predicted tacrolimus AUC(0-12) (AUCp) was calculated using the following: (i) 42 multiple regression-derived limited sampling strategies (LSSs); (ii) five population pharmacokinetic (PK) models in the Bayesian forecasting program TCIWorks; and (iii) a Web-based consultancy service. Correlations (r(2)) between C(0) and AUCf and between AUCp and AUCf were examined. Median percentage prediction error (MPPE) and median absolute percentage prediction error (MAPE) were calculated.
  
  
  RESULTS
  Correlation between C(0) and AUCf was 0.53. Using the 42 LSS equations, correlation between AUCp and AUCf ranged from 0.54 to 0.99. The MPPE and MAPE were <15% for 29 of 42 equations (62%), including five of eight equations based on sampling taken ≤2 h post-dose. Using the PK models in TCIWorks, AUCp derived from only C(0) values showed poor correlation with AUCf (r(2)=0.27-0.54) and unacceptable imprecision (MAPE 17.5-31.6%). In most cases, correlation, bias and imprecision estimates progressively improved with inclusion of a greater number of concentration time points. When concentration measurements at 0, 1, 2 and 4 h post-dose were applied, correlation between AUCp and AUCf ranged from 0.75 to 0.93, and MPPE and MAPE were <15% for all models examined. Using the Web-based consultancy service, correlation between AUCp and AUCf was 0.74, and MPPE and MAPE were 6.6 and 9.6%, respectively.
  
  
  CONCLUSIONS
  Limited sampling methods better predict tacrolimus exposure compared with C(0) measurement. Several LSSs based on sampling taken 2 h or less post-dose predicted exposure with acceptable bias and imprecision. Generally, Bayesian forecasting methods required inclusion of a concentration measurement from >2 h post-dose to adequately predict exposure.
authors.affiliation: Department of Nephrology, University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD 4102, Australia. katherine_barraclough@health.qld.gov.au
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Barraclough
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Isbel
authors.forename: Carl M
authors.initials: CM
authors.lastname: Kirkpatrick
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Lee
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Taylor
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.forename: Scott B
authors.initials: SB
authors.lastname: Campbell
authors.forename: Diana R
authors.initials: DR
authors.lastname: Leary
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
mesh_terms: D000328:Adult; D001800:Blood Specimen Collection / Q000379:methods; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care / Q000379:methods; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus