title: Development and validation of limited sampling strategies for tacrolimus and mycophenolate in steroid-free renal transplant regimens.
abstract: OBJECTIVE
  1) To develop and validate limited sampling strategies (LSSs) for tacrolimus (TAC) and mycophenolic acid (MPA) in renal transplant recipients not receiving corticosteroids; and 2) to evaluate predictive performance of published LSSs (for steroid-based regimens) in a steroid-free population.
  
  
  METHODS
  On administration of steady-state morning TAC and mycophenolate mofetil doses, 12-hour serial blood samples from 28 stable renal transplant recipients were collected and measured by validated high-performance liquid chromatography methods and area under the curve (AUC) by trapezoidal rule. TAC LSSs were developed and validated by multiple regression analysis by a two-group method (index n = 18; validation n = 10) and MPA LSSs by the jackknife method (n = 28). Potential LSSs were those with r ≥ .8 (TAC) or r ≥ 0.7 (MPA) and < 3 time points within 2 hours (TAC) or 4 hours (MPA) postdose. Predictive performance was calculated and other published TAC and MPA LSSs tested using preset criteria for bias and precision of within ± 15%.
  
  
  RESULTS
  For TAC, three three-concentration, one two-concentration, and one one-concentration model met preset criteria. The best equations were: TAC AUC = 10.338 + 7.739C0 + 3.589C2 (r = 0.956, bias = -3.4%, precision = 4.7%) and TAC AUC = 29.479 + 5.016C2 (r = 0.862, bias = 3.2%, precision = 9.7%). For MPA, only one model was identified: MPA AUC = 9.328 + 1.311C1 + 1.455C2 + 2.901C4 (r = 0.838, bias = -3.8%, precision = 14.9%). One published TAC (and no MPA) LSS in renal transplant recipients on steroid-based regimens met criteria.
  
  
  CONCLUSIONS
  To the authors' knowledge, these LSSs are the first to be developed and validated in steroid-free renal transplant recipients and can be used to accurately predict TAC and MPA AUCs for steroid-free regimens. Because the commonly used MPA LSS is based on a steroid regimen and not predictive for steroid-free patients, the newly derived MPA LSS is being applied at the authors' institution. Other renal transplant centers may also wish to validate this equation in their own patients.
authors.affiliation: Pharmacy Department, Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Poulin
authors.forename: Erica D
authors.initials: ED
authors.lastname: Greanya
authors.forename: Nilufar
authors.initials: N
authors.lastname: Partovi
authors.forename: R Jean
authors.initials: RJ
authors.lastname: Shapiro
authors.forename: Mai
authors.initials: M
authors.lastname: Al-Khatib
authors.forename: Mary H H
authors.initials: MH
authors.lastname: Ensom
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001800:Blood Specimen Collection / Q000379:methods*; D003430:Cross-Sectional Studies; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011446:Prospective Studies; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus