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Background Approximately half of cyclosporine A-treated renal transplant recipients do not reach sufficient mycophenolic acid (MPA) exposure in the first weeks posttransplantation with standard MPA dosing regimens. Methods Here, we present a prospectively planned meta-analysis of data from two 6-month parallel-run studies that evaluated the effect of an initially intensified versus standard dosing regimen of enteric-coated mycophenolate sodium (EC-MPS). Four hundred forty-one de novo renal transplant recipients were randomized (1:1) to intensified (2 weeks 2880 mg/d; subsequently 4 weeks 2160 mg/d; followed by 1440 mg/d) or standard (1440 mg/d) EC-MPS, with concomitant cyclosporine A treatment and steroids with or without anti-IL-2R induction. Primary endpoint was treatment failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 6 posttransplantation. Results Treatment failure rates were 17.4% in intensified and 22.4% in standard groups (P=0.110). The incidence of BPAR was 13.8% (intensified) vs. 19.3% (standard; P=0.034). A total of 80.5% (intensified) versus 39.0% (standard) of patients achieved 12 hr MPA-area under the curve more than 30 μg·hr/mL as early as day 3 posttransplant. Renal function, gastrointestinal symptom rating scores, and safety profiles were comparable between treatment groups. Conclusion The initially intensified EC-MPS dosing regimen was associated with higher MPA exposure, significantly lower rate of BPAR, and comparable safety. However, the intensified regimen did not affect graft function or survival.

Introduction. Chronic allograft nephropathy is the main cause of long-term renal transplant failure. Chronic use of calcineurin inhibitors contributes to its pathogenesis. Here, we report on a multicenter randomized trial to study the effects of withdrawal of cyclosporine A (CsA) from a triple immunosuppressive regimen containing CsA, prednisolone (P), and mycophenolate sodium (MPS) early after transplantation.Methods. Patients continued on P/CsA, P/MPS, or P and everolimus (EVL). Before withdrawal, a transplant biopsy was performed ensuring no subclinical rejection was present. Drug levels were closely monitored. The primary outcome was interstitial graft fibrosis and hyalinosis. Secondary outcome was among others graft rejection.Results. According to trial regulations, an interim analysis was performed after enrollment of half of the intended number of patients (n = 113). Mean follow-up was 14 5 months from transplantation and 8 +/- 5 months from conversion. After conversion, acute rejection percentages were 3% in the P/CsA group, 22% in the P/MPS group, and 0% in the P/EVL group (PConclusions. We conclude that switching immunosuppressive therapy from P/CsA/MPS to therapy with P/CsA or P/EVL at 6 months after renal transplantation is effective in preventing rejection. Double therapy with P/MPS after withdrawal of P/CsA resulted in an increase in severe acute rejection episodes. These results were the immediate reason to halt the P/MPS arm. Serum creatinine values at the latest follow-up (8 +/- 5 months after conversion and 14 +/- 5 months after transplantation) in the P/EVL group were lower than in the P/CsA group.

Background Mycophenolic acid (MPA) is an inhibitor of lymphocyte proliferation and is well established as an immunosuppressive agent in solid organ transplantation. The initial formulation of the drug was a prodrug formulation, mycophenolate mofetil (MMF, Cellcept), which is well absorbed and rapidly converted to mycophenolate in plasma. However, the use of MMF is associated with adverse gastrointestinal events, which can lead to withdrawal of therapy. In an effort to reduce the gastrointestinal effects of MMF, an enteric-coated formulation of the drug was developed, based on the sodium salt of MPA (EC-MPS, Myfortic). Methods Although bioequivalence has been demonstrated in an individual study in maintenance kidney transplant patients, this manuscript documents bioequivalence in a much larger data set of 82 patients by a meta-analysis of data from clinical trials. Results The results confirm the bioequivalence of EC-MPS and MMF for both mycophenolate and metabolite exposure, and for maximum plasma mycophenolate concentrations, across three studies. The 90% confidence interval of the ratio of EC-MPS to MMF for mycophenolate plasma AUC in the 82 patients was 101.1 to 114.5% and for Cmax was 83.0% to 112.7%. Conclusion These findings provide reassurance to transplant professionals and patients that, when choosing between EC-MPS and MMF, they are choosing between formulations that give equivalent mycophenolate exposure.

Background. The benefit of converting renal transplant recipients with gastrointestinal (GI) complaints from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) has not been evaluated using patient-reported outcomes. Methods. A multicenter, open-label, prospective study was undertaken in MMF-treated renal transplant patients. Patients experiencing GI complaints were converted to equimolar EC-MPS (Cohort A). Patients without GI complaints remained on MMF (Cohort B). At baseline and Visit 2 (4-6 weeks postbaseline), patients completed the Gastrointestinal Symptom Rating Scale (GSRS), Gastrointestinal Quality of Life Index (GIQLI) and Psychological General Well-being Index (PGWBI). At Visit 2, patients and physicians completed the Overall Treatment Effect (OTE) scale for GI symptoms. Additionally, patients completed the OTE for health-related quality of life (HRQoL). Minimal important difference (MID) was calculated for GSRS and GIQLI based on patients' and physicians' OTE evaluation. Results. Of 328 patients enrolled (i.e. the intent-to-treat and safety populations), 278 formed the per-protocol population (Cohort A, n= 177; Cohort B, n=101). At baseline, Cohort A had significantly worse scores on all GSRS, GIQLI and PGWBI subscales compared to Cohort B (all P

Background, ERL is the enteric-coated sodium salt of mycophenolic acid, presently in clinical development. The drug substance mycophenolate sodium (MPS) was evaluated in rat transplantation models and compared with mycophenolate mofetil (MMF) for therapeutic window and synergy with cyclosporine (CsA). Methods. Allotransplantation was performed in the Dark Agouti-to-Lewis (DA-to-Lewis; kidney, heart, and aorta) and Brown Norway-to-Lewis (BN-to-Lewis; kidney) strain combinations, and hamster heart xenotransplantation was performed in athymic and euthymic Lewis rats. The compounds were administered daily orally, starting the day of transplantation. Results. In kidney and heart transplantation the minimal efficacious dose of CsA was 5.0 mg/kg/d. For MPS this dose was 10 mg/kg/d in BN-to-Lewis kidney transplantation, 20 mg/kg/d in DA-to-Lewis heart transplantation, and 10 mg/kg/d in hamster-to-athymic rat heart transplantation. At these doses the first signs of adverse effects were evident, indicating a narrow therapeutic window. No window was established for MMF in these models or for MPS in DA-to-Lewis kidney transplantation. There was no potential synergy between CsA and MPS or MMF regarding efficacy, but fewer side effects were noted in efficacious combinations, in particular for MPS. In aorta transplantation, MPS and MMF dose-dependently inhibited intima thickening. The combination of 20 mg/kg/d MPS and 10 mg/kg/d CsA gave long-term survival of hamster-to-rat xenografts. Conclusions. Despite the overall comparable efficacy and narrow therapeutic window of MPS and MMF when given alone, MPS apparently is better tolerated than MMF in some of the transplant models. The combination of these agents with CsA allows fine-tuning between optimal immunosuppression and adverse side effects.

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 μg-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

Background In renal transplant (RT) recipients, treatment with enteric-coated mycophenolate sodium (EC-MPS) improves gastrointestinal (GI) tolerability compared with mycophenolate mofetil (MMF). The impact of conversion from MMF to EC-MPS on patient's health-related quality of life (HRQoL) using GI-specific instruments has been scarcely evaluated in randomized trials. Methods The present randomized, multicenter, open-labeled, 12-week study included RT recipients experiencing GI adverse events due to MMF treatment. Patients were randomized to continue with MMF (n=54) or change to EC-MPS (n=59). Patients were converted at equimolar doses, and dose was optimized between weeks 2 and 6 to achieve maximum tolerated dose. Results Incidence of GI complications (particularly diarrhea) was significantly lower in the EC-MPS group (67.8% vs. 87.0%, P=0.015). The baseline-adjusted mean global scores at 12 weeks in GI quality of life index were significantly higher in the EC-MPS group versus MMF (P=0.014). Results at 12 weeks for all secondary scales indicated better HRQoL in the EC-MPS group compared with the MMF group (Gastrointestinal Symptom Rating Scale, Psychological General Well-Being Index, and overall treatment effect). In the EC-MPS group, a higher percentage of patients were receiving intermediate doses of mycophenolic acid (720 mg/day) at 12 weeks compared with MMF (55.4% vs. 27.4%, P=0.003), whereas no differences were observed for high doses (>720 mg/day). Conclusions In RT patients with GI undesirable effects due to MMF, switching from MMF to EC-MPS may enable an increase in the maximum tolerated dose of mycophenolic acid and reduce GI complications, thus enhancing patients' GI HRQoL.

Background Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (MMF) formulation are known to differ between patients receiving tacrolimus or cyclosporine, but only limited data exist concerning concomitant use of tacrolimus and enteric-coated mycophenolate sodium (EC-MPS). Methods In this six-month, multicenter, open-label, single-arm trial, 63 maintenance renal transplant patients receiving tacrolimus were converted from mycophenolate mofetil (MMF) to EC-MPS. Results MPA concentration-time profiles in 21 patients showed that MPA exposure was similar with MMF or EC-MPS (mean area under the curve 39.9+/-11.6 microg x h/mL versus 43.7+/-17.4 microg x h/mL at day 14 post-conversion). Median time to peak concentration was 0.5 hr with MMF and 1.5 hr with EC-MPS. Inosine monophosphate dehydrogenase (IMPDH) activity was almost identical: area under the enzyme activity time curve (AEC) was 124.2+/-32.0 nmol x h/mg prot/h with MMF and 130.3+/-36.6 nmol x h/mg prot/h with EC-MPS at 14 days post-conversion; average daytime IMPDH activity was 10.3+/-2.7 nmol/h/mg protein and 10.9+/-2.7 nmol/h/mg protein, respectively. Maximal daytime inhibition of IMPDH activity was 67% with MMF and 62% with EC-MPS at day 14. One patient (1.6%) experienced mild biopsy-proven acute rejection. No graft losses or deaths occurred. Renal function remained stable (mean calculated creatinine clearance 70.6+/-26.8 mL/min with MMF and 68.8+/-25.4 mL/min six months post-conversion). Adverse events or infections with a suspected relation to EC-MPS occurred in 12 patients (19%). Four patients discontinued EC-MPS due to adverse events or infections. Conclusions MMF and EC-MPS are associated with similar MPA exposure and equivalent pharmacodynamic effect. Conversion of tacrolimus-treated maintenance renal transplant patients from MMF to EC-MPS is safe and well-tolerated and does not compromise therapeutic efficacy.