title: A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation.
abstract: BACKGROUND
  Adding a fixed dose of 1 g b.i.d. of mycophenolate mofetil (MMF) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50% reduction in the incidence of acute rejection after kidney transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA AUC) and the prevention of rejection after kidney transplantation.
  
  
  METHODS
  A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were randomly allocated, in this double-blind trial, to receive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32.2, and 60.6 microg x hr/ml). During the first 6 months after transplantation, plasma samples for nine AUCs were collected. After analysis of the samples, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consisted of cyclosporine and prednisone. The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period.
  
  
  RESULTS
  A total of 150 patients were eligible for analysis. Although after day 21, the mean MMF dose was reduced, the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups. The incidences of biopsy-proven acute rejection in the low, intermediate, and high target MPA AUC groups were 14 of 51 (27.5%), 7 of 47 (14.9%), and 6 of 52 (11.5%), respectively. The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 (7.8%), 11 of 47 (23.4%), and 23 of 52 (44.2%), respectively. Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic regression using median ln(Cpredose) was also statistically significant for this relationship (P=0.01), whereas it was not when using mean MMF dose (P=0.082). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant (P<0.001), whereas this was not significant when using median ln(Cpredose) (P=0.512) or median ln(MPA AUC) (P=0.434).
  
  
  CONCLUSIONS
  MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.
authors.affiliation: Department of Internal Medicine I, University Hospital Rotterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van Gelder
authors.forename: L B
authors.initials: LB
authors.lastname: Hilbrands
authors.forename: Y
authors.initials: Y
authors.lastname: Vanrenterghem
authors.forename: W
authors.initials: W
authors.lastname: Weimar
authors.forename: J W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: J P
authors.initials: JP
authors.lastname: Squifflet
authors.forename: R J
authors.initials: RJ
authors.lastname: Hené
authors.forename: G A
authors.initials: GA
authors.lastname: Verpooten
authors.forename: M T
authors.initials: MT
authors.lastname: Navarro
authors.forename: M D
authors.initials: MD
authors.lastname: Hale
authors.forename: A J
authors.initials: AJ
authors.lastname: Nicholls
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood*; D015994:Incidence; D007668:Kidney / Q000502:physiology; D016030:Kidney Transplantation / Q000276:immunology*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D009894:Opportunistic Infections / Q000150:complications / Q000209:etiology; D010599:Pharmacokinetics; D010600:Pharmacology; D011241:Prednisone / Q000627:therapeutic use; D012720:Severity of Illness Index; D015996:Survival Rate
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D011241:Prednisone