title: Limited sampling strategies for monitoring tacrolimus in pediatric liver transplant recipients.
abstract: OBJECTIVE
  To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients.
  
  
  METHODS
  Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error.
  
  
  RESULTS
  Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84).
  
  
  CONCLUSIONS
  Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.
authors: Division of General Pediatric Surgery, Department of Surgery, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada.
authors: Jean-Romain
authors: JR
authors: Delaloye
authors: Nastya
authors: N
authors: Kassir
authors: Anne-Laure
authors: AL
authors: Lapeyraque
authors: Fernando
authors: F
authors: Alvarez
authors: Michel
authors: M
authors: Lallier
authors: Mona
authors: M
authors: Beaunoyer
authors: Line
authors: L
authors: Labbé
authors: Yves
authors: Y
authors: Théorêt
authors: Catherine
authors: C
authors: Litalien
mesh_terms: D000293:Adolescent; D001800:Blood Specimen Collection / Q000379:methods*; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics*; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D012044:Regression Analysis; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus