A RANDOMISED, DOUBLE-BLIND, PLASMA CONCENTRATION CONTROLLED STUDY OF THE SAFETY AND EFFICACY OF ORAL MYCOPHENOLATE MOFETIL FOR THE PREVENTION OF ACUTE REJECTION AFTER KIDNEY TRANSPLANTATION.

Whether drug monitoring will improve the efficacy and safety of MMF treatment after kidney transplantation (tx) is not known. This study was designed to investigate the relationship between pharmacokinetic data (mycophenolic acid area under the curve, MPA AUC) and the clinical outcome after kidney tx. 150 recipients of a cadaveric kidney graft were randomly allocated and received MMF aimed at 3 target MPA AUC values (16.1, 32.2 and 60.6 ug.h/ml). During the first 6 months after tx plasma samples for 9 AUC's were collected. After analysis a coded dose adjustment advice was generated using a Bayesian algorithm Drug treatment further consisted of CsA and prednisone. Target MPA AUC values were exceeded in all 3 groups and reached 27.6, 54.8 and 96.7 ug.h/ml at 6 months. The incidence of biopsy proven rejection (BPR) in the low, intermediate and high target MPA AUC group was 13/51 (25.5%), 4/47 (8.5%) and 3/52 (5.8%) resp. The incidence of premature withdrawal from the study due to adverse events in the 3 groups was 4/51 (7.8%), 11/47 (23.4%) and 23/52 (44.2%). Logistic regression analysis showed a highly statistically significant relationship between median natural logarithm (In) of MPA AUC and the occurrence of a BPR (P<O.OO1). The logistic regression using median ln(C_pre-dose) was also significant for this relationship (p=O.O1), whereas it was not when using mean MMF dose (p=O.O82). In contrast, the logistic regression using mean MMF dose for comparison of patients who successfully completed the study vs patients experiencing death or premature withdrawal due to adverse events was highly significant (P<O.OO1), whereas this was not significant when using median ln(C_pre-dose) or median In (MPA AUC). The results of MPA C_pre-dose and MPA AUC measurement are significantly related to the incidence of BPR after kidney tx, whereas MMF dose is significantly related to the occurrence of adverse events. The results of this study are of major relevance for designing studies evaluating the value of monitoring MPA concentrations after tx.

T.van Gelder^1,2, L.B. Hilbrands³, Y. Vanrenterghem⁴, W Weimar², J W. de Fijter⁵, J.P Squifflet⁶, R J. Hene⁷, G. Verpooten⁸, M.D. Hale⁹, A.J. Nlcholls¹⁰, University Hospitals of Rotterdam², Nijmegeri³, Leuven⁴, Leiden⁵, Brussels⁶, Utrecht⁷, Antwerp⁸, The Netherlands & Belgium, Roche Global Development ^9,10, Palo Alto, California¹. This study was sponsored by Roche.