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

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 kidne y transplantation. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve; MPA A UG) and the prevention of rejection after kidney transplantation. Methods. A total of 154 adult recipients of a primary or secondary cadaveri c kidney graft were randomly allocated, in this double-blind trial, to rece ive MMF treatment aimed at three predefined target MPA AUC values (16.1, 32 .2, and 60.6 mu g . hr/ml). During the first 6 months after transplantation , plasma samples for nine AUCs were collected. After analysis of the sample s, a coded dose adjustment advice was generated using a Bayesian algorithm, maintaining the double blinding. Immunosuppressive therapy further consist ed of cyclosporine and prednisone, The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study pe riod. 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 increase d and target MPA AUC values were exceeded in all three groups. The incidenc es of biopsy-proven acute rejection in the low, intermediate, and high targ et 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 In(MPA AUG) and the occurrence of a biopsy-proven rejection (P<0.001). The logistic reg ression using median In(C-predose) was also statistically significant for t his 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 compari son of patients who successfully completed the study versus patients experi encing premature withdrawal due to adverse events was highly significant (P <0.001), whereas this was not significant when using median In(C-predose) ( P=0.512) or median In(MPA AUG) (P=0.434). Conclusion. MPA C-predose and MPA AUC are significantly related to the inci dence of biopsy-proven rejection after kidney transplantation, whereas MMF dose is significantly related to the occurrence of adverse events.