title: Time to reach tacrolimus maximum blood concentration,mean residence time, and acute renal allograft rejection: an open-label, prospective, pharmacokinetic study in adult recipients.
abstract: OBJECTIVE
  The aims of this study were to determine whether disposition-related pharmacokinetic parameters such as T(max) and mean residence time (MRT) could be used as predictors of clinical efficacy of tacrolimus in renal transplant recipients, and to what extent these parameters would be influenced by clinical variables.
  
  
  METHODS
  We previously demonstrated, in a prospective pharmacokinetic study in de novo renal allograft recipients, that patients who experienced early acute rejection did not differ from patients free from rejection in terms of tacrolimus pharmacokinetic exposure parameters (dose interval AUC, preadministration trough blood concentration, C(max), dose). However, recipients with acute rejection reached mean (SD) tacrolimus T(max) significantly faster than those who were free from rejection (0.96 [0.56] hour vs 1.77 [1.06] hours; P < 0.001). Taking into account that neither differences in tacrolimus steady-state clearance nor T(1/2) could explain this unusual finding, we used data from the previous study to calculate MRT from the concentration-time curves.
  
  
  RESULTS
  As part of the previous study, 100 patients (59 male, 41 female; mean [SD] age, 51.4 [13.8] years;age range, 20-75 years) were enrolled in the study The calculated MRT was significantly shorter in recipients with acute allograft rejection (11.32 [031] hours vs 11.52 [028] hours; P = 0.02), just like T(max) was an independent risk factor for acute rejection in a multivariate logistic regression model (odds ratio, 0.092 [95% CI, 0.014-0.629]; P = 0.01). Analyzing the impact of demographic, transplantation-related, and biochemical variables on MRT, we found that increasing serum albumin and hematocrit concentrations were associated with a prolonged MRT (P < 0.05). Conversely, serum albumin and hematocrit concentrations were significantly lower in recipients with acute rejection (P < (101).
  
  
  CONCLUSIONS
  In this selected population of de novo renal allograft recipients, a shorter tacrolimus T(max) and calculated MRT were associated with a higher incidence of early acute graft rejection. These findings suggest that a shorter transit time of tacrolimus in certain tissue compartments, rather than failure to obtain a maximum absolute tacrolimus blood concentration, might lead to inadequate immunosuppression early after transplantation.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
authors.forename: Dirk R J
authors.initials: DR
authors.lastname: Kuypers
authors.forename: Yves
authors.initials: Y
authors.lastname: Vanrenterghem
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016903:Drug Monitoring; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis* / Q000517:prevention & control; D006400:Hematocrit; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D011446:Prospective Studies; D012709:Serum Albumin / Q000378:metabolism; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D012709:Serum Albumin; D016559:Tacrolimus