title: Best single time points to predict the area-under-the-curve in long-term heart transplant patients taking mycophenolate mofetil in combination with cyclosporine or tacrolimus.
abstract: BACKGROUND
  The use of C2 levels for therapeutic drug monitoring (TDM) of cyclosporine microemulsion (CsA) has been clinically validated. Routine TDM of tacrolimus and mycophenolate mofetil (MMF) is based on trough (C0) levels and side effects, respectively. The purpose of the present study was to determine the best single time points to assess the area-under-the-curve (AUC(0-12 hours)) in long-term heart transplant patients being treated with MMF in combination with CsA or tacrolimus.
  
  
  METHODS
  We studied the AUC(0-12 hours) in long-term (>1 year), adult heart transplant patients being treated with CsA and MMF (14 patients) and with tacrolimus and MMF (9 patients).
  
  
  RESULTS
  C2 is the best surrogate (r2 = 0.87) of CsA AUC(0-12 hours). Tacrolimus C1 (r2 = 0.78), C2 (r2 = 0.83), C3 (r2 = 0.89) and C4 (r2 = 0.92) correlate better than C0 (r2 = 0.51) with the AUC(0-12 hours). When MMF is combined with CsA, there is poor correlation (r2) of MPA at all measured time points (C0 = 0.49, C2 = 0.09, C3 = 0.23, C4 = 0.44, and C6 = 0.60). When MMF is combined with tacrolimus, MPA C2 (r2 = 0.72), C4 (r2 = 0.86), C6 (r2 = 0.85), and C8 (r2 = 0.93) are better surrogates of the AUC(0-12 hours) compared with C0 (r2 = 0.69).
  
  
  CONCLUSIONS
  Our results suggest that in long-term heart transplant patients, the calcineurin inhibitor used in combination with MMF affects the correlation between MPA single time points and the AUC(0-12 hours). Future studies should determine the clinical benefit of TDM of tacrolimus and MPA with C2 or C4 compared with C0 and determine the therapeutic ranges. As for CsA-treated patients, CsA TDM should be performed with C2, and the TDM of MMF may be clinically irrelevant.
authors.affiliation: Department of Medicine, Royal Victoria Hospital, McGill University Health Center, Montréal, Québec, Canada.
authors.forename: Vartan
authors.initials: V
authors.lastname: Mardigyan
authors.forename: Nadia
authors.initials: N
authors.lastname: Giannetti
authors.forename: Renzo
authors.initials: R
authors.lastname: Cecere
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Besner
authors.forename: Marcelo
authors.initials: M
authors.lastname: Cantarovich
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D065095:Calcineurin Inhibitors; D009202:Cardiomyopathies / Q000601:surgery; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006331:Heart Diseases / Q000601:surgery; D006338:Heart Neoplasms / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus