title: Pharmacokinetic modeling and development of Bayesian estimators in kidney transplant patients receiving the tacrolimus once-daily formulation.
abstract: BACKGROUND
  The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation cannot be used for the new once-daily formulation. Using the PK information obtained from a Phase II trial, the aim of this study was to explore the feasibility of developing a PK model and a MAP-BE able to estimate, on the basis of a routinely applicable limited sampling strategy, tacrolimus individual PK parameters and AUC0-24h in de novo renal transplant patients given the once-daily formulation.
  
  
  METHODS
  Twelve de novo kidney transplant recipients receiving once-daily tacrolimus as part of their immunosuppressive regimen provided full PK profiles (17 concentration time points over 24 hours) on Days 14 and 42 posttransplantation. On the basis of a one-compartment open model with absorption described as following a double gamma distribution, a classic iterative two-stage method was applied to develop MAP-BEs. All the limited sampling strategies with a maximum of three sampling times within 4 hours postdose were tested for Bayesian forecasting with the aim of accurately estimating the AUC0-24h.
  
  
  RESULTS
  Once-daily tacrolimus exhibited a high interpatient PK variability with coefficients of variation of 34.3% and 36.2% for AUC0-24h/dose (mg/kg) on Days 14 and 42, respectively. Regression analysis between C0 and AUC0-24h yielded r = 0.68 and 0.76 at these two periods, respectively. The iterative two-stage approach led to the development of a different MAP-BE for each posttransplantation period, which allowed estimation of once-daily tacrolimus pharmacokinetics and AUC0-24h on the basis of a C0-C1h-C3h sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 4.2% +/- 6.1% (range, -11.8% to +11.2%; root mean square error = 7.1%) on Day 14 and 0.2% +/- 7.9% (range, -12.9% to +14.1%; root mean square error = 7.8%) on Day 42.
  
  
  CONCLUSIONS
  A PK model and Bayesian estimators allowing estimation of tacrolimus AUC0-24h based on a routinely applicable limited sampling strategy were developed for once-daily tacrolimus in renal transplantation. Further validation in independent groups of patients is required to confirm their applicability for optimizing the monitoring of once-daily tacrolimus in routine clinical practice or to conduct observational or comparative therapeutic drug monitoring clinical trials.
authors.affiliation: INSERM UMR-S850, Limoges, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Saint-Marcoux
authors.forename: Jean
authors.initials: J
authors.lastname: Debord
authors.forename: Nasrullah
authors.initials: N
authors.lastname: Undre
authors.forename: Annick
authors.initials: A
authors.lastname: Rousseau
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
mesh_terms: D001499:Bayes Theorem; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008956:Models, Chemical; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D016559:Tacrolimus