The Value of Routine Monitoring of Mycophenolic Acid Plasma Levels After Clinical Heart Transplantation C.J. Hesse, P. Vantrimpont, I.C. van Riemsdijk-van Overbeeke, T. van Gelder, A.H.M.M. Balk, and W. Weimar M YCOPHENOLATE MOFETIL (MMF), an ester prodrug of the immunosuppressive agent mycophe- nolic acid (MPA), is increasingly being used in conjunction with the calcineurin inhibitors cyclosporin (CsA) or tacroli- mus (TAC) to prevent acute rejection after organ trans- plantation. From the results of three multicentre studies on MMF in renal transplantation, it was concluded that the optimal daily dose of MMF, when administered from the time of transplantation, is 2 g. 1–3 For heart transplant patients a higher dose possibly is needed. In this study we want to evaluate the need for routine monitoring of MPA trough plasma levels to prevent acute rejection in heart transplant recipients. Therefore, MPA and CsA concentra- tions, measured in blood samples collected at the time of endomyocardial biopsies, were retrospectively analysed and results of drug concentrations were correlated with biopsy histology scores in this cohort of heart transplant recipients. Conversion of some patients from CsA to TAC offered the opportunity to analyse the influence of CsA or TAC on MPA levels. PATIENTS AND METHODS The study group consisted of a cohort of 20 cardiac allograft recipients in whom a total of 147 endomyocardial biopsies were performed according to standard biopsy schedules or when indi- cated by clinical suspicion of rejection. All biopsies were obtained during the first year after transplantation. Biopsy specimens were graded according to the standardised criteria of the International Society for Heart and Lung Transplantation. MMF was adminis- tered orally at a dose of 1500 mg twice daily in addition to standard CsA and prednisone therapy. Based on clinical symptoms MMF dose reductions were performed in some patients during the study period. Four patients, suffering from hypertension, renal insuffi- ciency, or neurotoxicity, were converted from CsA to TAC. Rou- tine whole blood monitoring of trough levels of CsA (EMIT, Syva Dade Behring, Cupertino, Calif, USA) or TAC (IMx TAC II, Abbott Laboratories, Abbott Park, Ill, USA) were performed according to the manufacturers’ recommendations. CsA doses were adjusted to reach whole blood target levels of 200 to 350 ng/mL in the first 6 months after transplantation and 150 to 200 ng/mL thereafter. Twelve-hour trough MPA plasma concentration were determined using the mycophenolic acid assay (EMIT, Syva Dade Behring, Cupertino, Calif, USA) on a Cobas Mira Plus analyser (Roche Diagnostic Systems, Basel, Switzerland). Statisti- cal tests used were one-way ANOVA (Kruskal-Wallis with Dunn’s posttest) and Mann-Whitney test. Significance for all analyses was set at P  .05. RESULTS The mean follow-up time after transplantation in the group of 20 patients was 10.1 months. In 54 endomyocardial biopsy specimens no evidence of rejection (grade 0) was found; 61 biopsy specimens showed grade 1A, 16 grade 2, and 16 grade 3A. Only grade 3A biopsies were treated with antirejection therapy. During this first year after heart transplantation nine patients remained free from rejection and 11 patients had one or two rejection episodes. The median concentrations of all samples of CsA and MPA were 240 ng/mL (25% and 75% percentile, 200 and 292 ng/mL) and 1.51 mg/L (25% and 75% percentile, 0.96 and 2.23 mg/L), respectively. A significant difference was found between the median of all MPA concentrations of the patients with acute rejection (AR), 1.36 mg/L (range, 0.26 to 6.13 mg/L), and the patients without AR, 1.76 mg/L (range, 0.49 to 7.65; Mann-Whitney test, P = .015). No significant differences were found in CsA levels in the patients with AR and the patients without AR (median, 240 ng/mL; range, 80 to 460 ng/mL vs 263 ng/mL; range, 120 to 730 ng/mL, respectively). After grouping the CsA and the MPA results according to the score of the simultaneously obtained biopsies, no significant difference (P = .28) in CsA or MPA (P = .91) levels (Fig 1) was found between the different categories of biopsies (Kruskall-Wallis). To test for a combined effect of CsA low level and MPA low level, CsA and MPA concentrations were multiplied, and these values were tested for differences between the groups. Again no significant (P = .48) difference was found in the values between the different categories of biopsy scores. Five patients underwent an MMF dose adjustment during the study period. The resulting MPA plasma concentrations proved the existence of a linear relationship between the From the Department of Internal Medicine and Thorax Center, Erasmus University, and University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands. Address reprint requests to Dr C.J. Hesse, University Hospital Rotterdam-Dijkzigt, Department of Internal Med, Rm BD299, PO Box 2040, 3000 CA Rotterdam, Netherlands. © 2001 by Elsevier Science Inc. 0041-1345/01/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0041-1345(01)01927-3 Transplantation Proceedings, 33, 2163–2164 (2001) 2163