Stable renal transplant recipients can be safely converted from MMF to enteric-coated mycophenolate sodium tablets: Interim results of a multicenter Latin American study

Enteric-coated mycophenolate sodium (EC-MPS) is designed to reduce mycophenolate acid (MPA)-related upper gastrointestinal (GI) adverse events (AEs). A multicenter, open-label, Latin American study in stable renal transplant patients is ongoing to assess the safety of the conversion from mycophenolate mofetil (MMF) to EC-MPS. An interim analysis was performed when 93 patients had completed 3 months. Prior to conversion, they had received MMF at a dose of 2 g/d, with the exception of eight adult patients who were receiving an average daily dose of 1.25 g. All adult patients were converted to EC-MPS (1.44 g/d; 0.450 g/m(2) bid for children). After conversion, the reported total incidence of AEs was 40.9%, including 28% infections, 1.1% hematologic, 19.4% GI, including 10.8% upper-GI AE (all mild) and 5.4% diarrhea. No patient discontinued the study medication due to adverse events. Only six patients (6%) required a dose adjustment. There were no episodes of acute rejection, death, or graft loss. During the period of analysis, the conversion from MMF to EC-MPS was safe, the enteric-coated tablet formulation prevented release of MPA in the upper GI tract, and only one patient had to reduce the dose due to an upper GI AE, concomitant with diarrhea. EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF, but in a formulation that may provide GI tolerability benefits.     

Improvement of gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients

As many as 50% of liver transplant patients suffer gastrointestinal (GI) disturbances post-transplant. Conversion from mycophenolate mofetil (MMF) to mycophenolate sodium (EC-MPS) alleviates GI symptom burden in renal transplant recipients. We employed a validated patient and physician-reported assessment to evaluate the impact of conversion to EC-MPS in liver transplant patients. This is a prospective, longitudinal, single-center, open-label pilot study. Thirty-one MMF-treated liver transplant patients with GI symptoms were converted to equimolar EC-MPS. Gastrointestinal Symptom Rating Scale (GSRS), GI Quality of Life, SF-12v2 and physician-reported assessments were used to evaluate GI symptom burden and severity. A significant improvement in overall GSRS score was noted from baseline (2.57; 95% CI 2.12-3.10) to one month (1.90; 1.68-2.12; p = 0.0007) and three months (1.82; 1.60-2.04; p = 0.0002) post-conversion with significant reductions in all subgroups except Reflux. The overall Gastrointestinal Quality of Life Index (GIQLI) score also showed significant increase in health-related quality of life between one month (90.89; 84.04-97.75) and three months (100.04; 94.57-105.51; p = 0.0009), with all subgroups except social functioning (p = 0.0861) and medical treatment (p = 0.3156) demonstrating significant improvements. This pilot study demonstrates improvement in GI symptom burden when converting from equimolar doses of MMF to EC-MPS. This benefit persisted for three months without evidence of rejection.     

Better mycophenolic acid 12-hour trough level after enteric-coated mycophenolate sodium in patients with gastrointestinal intolerance to mycophenolate mofetil

INTRODUCTION: Enteric-coated mycophenolate sodium (EC-MPS) is the enteric-coated salt form of mycophenolic acid (MPA), the active component of the prodrug mycophenolate mofetil. EC-MPS was developed to reduce the upper-gastrointestinal (GI) effects of mycophenolate mofetil. There are no studies available comparing trough plasma levels in patients with GI intolerance to MMF when they are converted to EC-MPS. AIM: To compare the GI tolerance and the MPA levels in patients previously treated with MMF in whom this drug was replaced by EC-MPS. MATERIALS AND METHODS: A prospective study was conducted in 133 renal transplant patients after conversion from MMF to EC-MPS (median time posttransplant 42 months, range 1 to 240 months). The causes for EC-MPS switching were GI intolerance to MMF (51.9%; group A), low trough plasma levels with MMF (29.3%; group B), and others (18.8%; group C). These patients were converted to equipotent doses of EC-MPS. RESULTS: The trough plasma MPA levels increased from 1.5 +/- 1.1 microg/mL at baseline to 2.5 +/- 2.0 microg/mL at 1 month postconversion despite the equipotent EC-MPS doses not being increased. These higher plasma levels were maintained throughout the study. In group A, this increase was from 1.8 +/- 1.0 to 2.7 +/- 2.1 microg/mL (P = .01) and in group B from 0.8 +/- 0.4 to 2.4 +/- 1.4 microg/mL (P < .001). The doses and levels of calcineurin inhibitor decreased from baseline. Creatinine clearance improved from 56.5 +/- 24.7 mg/dL at baseline to 61.9 +/- 28.6 at 6 months postconversion (P = .02). There was a statistically significant increase in hemoglobin levels. In group A, the GI tolerance improved in 78% of the patients. CONCLUSIONS: At equipotent doses, patients converted to EC-MPS have higher and more adequate levels of MPA. At 6 months postconversion, we observed an improvement of the renal function, probably due to a reduction of calcineurin inhibitor drugs. However, the possibility that a better immunosuppressive efficacy as demonstrated by more suitable trough plasma levels may have been a contributing factor cannot be discarded.     

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant recipients with gastrointestinal tract disorders

OBJECTIVE: The objective of this prospective study was to evaluate the effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in renal transplant recipients with gastrointestinal tract (GI) reverse effects using patient-reported outcomes instrument. METHODS: A multicenter, open-label, prospective study was undertaken in renal transplant recipients treated with MMF. In patients experiencing GI tract symptoms, treatment was changed to equimolar EC-MPS (myfortic). At baseline and visit 2 (4-6 weeks after baseline), patients completed the Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI), and physicians completed the Overall Treatment Effect (OTE) scale at visit 2. A difference of 0.5 or greater in the OTE score is indicative of clinical relevance. RESULTS: Of 154 patients screened, 118 fulfilled the inclusion or exclusion criteria. Eighty-five men and 33 women with a mean age of 41.6 years participated in this study. Median time since transplantation was 12 months. Mean (SD) dose of MMF reported at baseline was 1209.4 (422.89) mg/d. More than 50% of patients reported MMF-associated nausea, dyspepsia, and abdominal pain. After conversion to an equimolar dose of EC-MPS, patients showed improvement in GI symptoms. This benefit was predominantly observed in patients with moderate to severe symptoms at baseline. On the GSRS, patients reported a significant (P < .05) reduction in symptom burden across all parameters (reflux, 36%; diarrhea, 38%; indigestion, 36%; constipation, 28%; and abdominal pain, 40%). On the GIQLI also, significant (P < .05) improvement was reported (symptoms, 18%; emotional status, 22%; physical functioning, 21%, and use of medical treatment, 18%). On the OTE scale, 84.7% of patients reported improvement in GI symptoms. CONCLUSION: In patients with moderate to severe GI symptoms, changing treatment from MMF to EC-MPS significantly reduces GI-related symptom burden and improves GI-specific quality of life.     

Enteric-coated mycophenolate sodium experience in liver transplant patients

Mycophenolate sodium (EC-MPS) has been shown to be as effective and as safe as mycophenolate mofetil (MMF) in renal transplant patients. Nevertheless, compared to MMF its use in liver transplant patients has been limited. The purpose of this study was to analyze the efficacy of EC-MPS as a primary immunosuppressant or as a replacement for MMF in liver transplant patients. Ninety among 470 liver transplant recipients were receiving or had added an antimetabolite to their immunosuppressant therapy. The most common reason for this change was renal dysfunction (47.8%) or diabetes (32.2%). EC-MPS was started at a median of 30 months after liver transplantation. The mean administered daily dose was 720 mg/d. At least one gastrointestinal symptom was reported by 25 patients. Abdominal pain (16.6%) and diarrhea (14.5%) were the most frequent. EC-MPS had to be discontinued in two patients, while six others required dose reduction to resolve the symptoms. Hematological adverse events were infrequent: three patients had leukopenia and one, anemia, all of which responded to dosage reduction. There was a creatinine reduction within 6 months of drug commencement and maintenance of the lower creatinine levels at 1 year among patients who began EC-MPS for renal dysfunction. Serum low-density lipoprotein cholesterol and triglyceride levels were significantly lower among patients on EC-MPS than on MMF. In conclusion, EC-MPS appears to have a similar efficacy and safety profile as MMF in liver transplant patients. Hematological and gastrointestinal adverse events were infrequent; seldom had the drug to be discontinued.     

Questionnaire-based evaluation of gastrointestinal disorders in de novo renal-transplant patients receiving either mycophenolate mofetil or enteric-coated mycophenolate sodium.

BACKGROUND: Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of our prospective questionnaire-based study was to assess GI side-effects in de novo renal-transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). METHODS: Between January 2002 and April 2003, all patients receiving MPA with a functioning allograft at 1 month post-transplantation were enrolled in this study (n = 130). Ninety-three of them received MMF (group I), and 37 patients received EC-MPS (group II). Each month, every patient completed a questionnaire regarding GI disorders. RESULTS: During the first year post-transplantation, GI disorders occurred in 31 patients from the MMF group (33.3%) and 12 patients from the EC-MPS group (32.4%) (not significant). The incidence of upper GI disorders was also similar in both groups. Diarrhoea was observed in 18 patients (19.3%) from group I, and in five patients from group II (13.5%) (not significant). Its frequency and severity were similar in both groups. Weight loss was observed in three patients receiving MMF. Diarrhoea resolved spontaneously in 10 patients from group I and in all patients from group II. For the other eight patients in group I, the diarrhoea required MMF discontinuation in three patients and dose reduction in five patients. CONCLUSIONS: In conclusion, in this questionnaire-based evaluation, the incidence of GI disorders was similar in patients receiving either MMF or EC-MPS during the first year post-transplantation.     

Enteric-Coated Mycophenolate Sodium: One-Way Conversion From Mycophenolate Mofetil and De Novo Use in Stable Liver Transplant Recipients

Enteric-coated mycophenolate sodium (EC-MPS) is a formulation of mycophenolic acid (MPA) that releases the active molecule in the intestine reducing drug-related gastrointestinal (GI) side effects. The aim of present work was to summarize the use of EC-MPS for one-way conversion from mycophenolate mofetil (MMF) due to GI side effects and for de novo administration in a stable liver transplant population. In 10 patients on MMF and low-dose calcineurin inhibitors (CNI), significant GI side effects suggested drug conversion to ameliorate subjective symptoms. In 5 patients, EC-MPS was initiated de novo together with reduction of CNI for prevention of long-term renal failure. Conversion was carried out at equivalent MMF/EC-MPS dosages. Reevaluation at 2 months after conversion showed that no episode of rejection or infection occurred, and white blood cell count, CNI levels and doses, and creatinine clearance did not vary significantly. In 70% of converted patients there was a reduction of GI symptoms, especially diarrhea. Eighty percent suspended proton pump inhibitors. The de novo-treated patients showed no significant GI side effects. In conclusion, conversion from MMF to EC-MPS demonstrated significant GI symptom relief and de novo drug administration was well tolerated.     

Clinical evolution in the first 3 months of patients after liver transplantation in maintenance phase converted from mycophenolate mofetil to mycophenolate sodium due to gastrointestinal complications

The enteric-coated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid with a gastro-resistant enteric coating, which releases the drug in the intestine, reducing the incidence of the gastrointestinal (GI) adverse effects. The present work provided a summary of 20 patients with liver transplantation and more than a 1 year of treatment with mycophenolate mofetil (MMF) who, after presentation of GI complications, were converted to EC-MPS. The patients were followed over a 3-month period after beginning EC-MPS treatment. The mean age of the cohort was 53 +/- 10 years and included 75% men. The reasons for transplantation were ethanol cirrhosis (70%), hepatitis C cirrhosis (30%), hepatocarcinoma (5%), and Wilson's disease (5%). At baseline, all patients were being treated with cyclosporine (CsA). CsA doses and levels were reduced during follow-up: baseline dose 179 mg/day versus 143 mg/day at 3 months; levels: 90.4 ng/mL versus 85.8 ng/mL, respectively (P = .017). The administered dose of EC-MPS was 720 mg/day in all cases. The GI complications at baseline were: diarrhea 60% (92% moderate-severe), abdominal discomfort 60% (58% moderate), abdominal pain 45% (44% moderate-severe), gas 40% (38% moderate-severe), nausea 20% (25% moderate), and dyspepsia 20% (mild). After 3 months of EC-MPS treatment, only two patients (10%) displayed moderate diarrhea. The renal evolution was favorable, serum creatinine was reduced, and 24-hour creatinine clearance significantly increased (creatinine: 1.78 +/- 1.6 mg/dL at baseline versus 1.30 +/- 0.3 mg/dL at 3 months, P = .002; creatinine clearance: 72.8 +/- 18 mL/min versus 79.6 +/- 13 mL/min, P = .001). Conversion of MMF to EC-MPS in liver transplant recipients solved the GI tolerability problems and improved renal function during the first 3 months, probably due to the concomitant reduction of anticalcineurinic dose.     

Conversion to enteric-coated mycophenolate sodium from various doses of mycophenolate mofetil: results of a prospective international multicenter trial in maintenance renal transplant patients receiving cyclosporine

Conversion from mycophenolate mofetil (MMF, CellCept) to enteric-coated mycophenolate sodium (EC-MPS, myfortic) is safe and effective in renal transplant patients treated with the standard dose of 2 g MMF. In this 6-month, international, multicenter, open-label, single-arm trial, a large cohort of maintenance renal transplant patients receiving different doses of MMF were converted under normal clinical conditions to equimolar doses of EC-MPS. Mean calculated creatinine clearance remained stable from the time of study entry (59.6 +/- 19.7 mL/min) to the end of the study (58.3 +/- 19.8 mL/min). Adverse events were reported by 152 patients (67%), with gastrointestinal complications being observed in 45 patients (20%). Thirty-three patients (15%) experienced adverse events or infections with a suspected relation to EC-MPS, including one case of anemia and two cases of leukopenia. Eleven patients (4.9%) required a reduction in EC-MPS dose and seven patients (3.1%) permanently discontinued EC-MPS owing to adverse events. At month 6 after conversion, five patients (2.2%) experienced biopsy-proven acute rejection. There were no graft losses or deaths. These data support earlier findings that stable maintenance renal transplant patients receiving MMF with cyclosporine with or without corticosteroids can be converted to EC-MPS with no compromise in efficacy and tolerability, and no adverse effect on renal function.     

Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPA, myfortic)

AIM: A 12-month multicenter, double-blind trial in which maintenance renal transplant patients were randomized to remain on mycophenolate mofetil (MMF) or convert to enteric-coated mycophenolate sodium (EC-MPS, myfortic) has demonstrated that conversion from MMF to EC-MPS is safe. Patients completing the study were invited to enter an open-label extension. Upon entry to the extension, patients who had received MMF during the randomized phase were converted to EC-MPS ("newly-exposed EC-MPS" group) and were monitored separately from those who had been randomized to EC-MPS ("long-term EC-MPS" group). The aim of the extension study was to collect long-term safety and efficacy data on EC-MPS, and to confirm the safety of conversion from MMF to EC-MPS in a larger patient population. METHODS: All patients received EC-MPS 720 mg b.i.d. with cyclosporine microemulsion and corticosteroids per local practice. Data derived from the analysis of the first 24 months of the extension phase are presented. RESULTS: Of the 297 patients who completed the core study, 260 (88%) entered the extension; 195 (75%) completed the 24-month extension visit. For on-treatment patients > 95% of the planned daily dose of EC-MPS was administered, and < 13% of patients in both groups had discontinued EC-MPS due to adverse events by 24 months. The overall incidence of adverse events during the extension phase, including infections and hematological abnormalities, was comparable to that seen in the core study, with a similar safety profile in the newly-exposed and long-term EC-MPS groups. There were 3 deaths during the first 24 months of the extension, and 2 graft failures in both the "newly-exposed" and "long-term" EC-MPS groups. CONCLUSIONS: These data demonstrate that long-term use of EC-MPS is effective and has an acceptable tolerability profile in renal transplant patients, and confirm that conversion of maintenance renal transplant patients from MMF to EC-MPS is a safe therapeutic option.     

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable maintenance renal transplant patients: pooled results from three international, multicenter studies

BACKGROUND: Mycophenolate mofetil (MMF) is effective in renal transplant patients but concerns remain over its gastrointestinal (GI) tolerability. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) has been developed with the intention of improving mycophenolic acid-related GI tolerability. METHODS: Data were pooled in a planned analysis of three subprotocols of the myfortic Prospective Multicenter Study (myPROMS). In a 6-month study, efficacy and safety of converting stable renal transplant recipients from MMF to a bioequivalent dose of EC-MPS for mycophenolic acid exposure were evaluated. Treatment efficacy was recorded and graft function was assessed by measuring serum creatinine and estimating creatinine clearance. Adverse events (AEs) and infections were monitored and the incidence of EC-MPS dose changes was recorded. RESULTS: A total of 588 patients were recruited, 564 (96%) of whom completed the study. The rate of treatment failure (defined as biopsy-proven acute rejection, graft loss, or death) was 1.9%, with no episodes of graft loss and only one death reported during the study. Renal function remained stable throughout the trial. EC-MPS was well tolerated; the majority of AEs were mild or moderate in severity. Dose reductions or interruptions were required by 6.3% and 1.9% of patients, respectively. Gastrointestinal AEs occurred in 138 patients (23.5%). The rate of dose adjustment as a result of a GI AE was 2.2%. CONCLUSIONS: Equimolar conversion from MMF to EC-MPS in maintenance renal transplant patients was safe and maintained efficacy.     

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P  < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients ( P  = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.     

Renal transplant patients with gastrointestinal intolerability to mycophenolate mofetil: conversion to enteric-coated mycophenolate sodium

The introduction of mycophenolate mofetil (MMF) was an important advance in immunosuppressive therapy, although its use is limited by adverse gastrointestinal events. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) has been developed to avoid these side effects. Recent clinical trials have demonstrated that EC-MPS is a safe drug in both de novo and maintenance renal transplant patients. In this prospective study, therapeutically equivalent doses of EC-MPS were administered to 39 stable kidney transplant patients receiving MMF. After 3 months of treatment with EC-MPS the incidence of adverse gastrointestinal events was lower (15.8% of the patients). There were higher levels of mycophenolic acid after conversion to EC-MPS, probably due to better absorption. These factors allowed decreased doses and levels of calcineurin inhibitors without increasing the risk of graft rejection. At 3 months postconversion, serum creatinine improved from the mean baseline value of 1.83 +/- 0.12 mg/dL to 1.70 +/- 0.10 mg/dL. In conclusion, EC-MPS was well tolerated in maintenance renal transplant patients with adverse gastrointestinal events secondary to MMF.     

Early experience with enteric-coated mycophenolate sodium in de novo kidney transplant recipients

INTRODUCTION: We sought to evaluate the efficacy of enteric-coated mycophenolate sodium (EC-MPS) and the gastrointestinal (GI) adverse events in de novo kidney transplant recipients. METHODS: This noncontrolled, retrospective review includes 22 de novo kidney transplant recipients. All patients received a standard course of basiliximab and were maintained on triple-drug therapy with EC-MPS, cyclosporine microemulsion (CsA), and prednisolone. The follow-up lasted 7.9 +/- 1.2 months. The incidence of GI adverse effects were compared with those of historical mycophenolate mofetil (MMF) studies. RESULTS: The serum creatinine was maintained within 1.4 +/- 0.7 mg/dL. The 2-hour CsA postdose level was 1080 +/- 327 ng/mL initially and gradually tapered to 851 +/- 435 ng/mL. The daily EC-MPS dose was 1404 +/- 180 mg initially and gradually tapered to 1098 +/- 288 mg. The GI adverse effects at the daily dose of EC-MPS 1422 +/- 126 mg included dyspepsia 27%, acid regurgitation 18.2%, epigastralgia 9%, nausea 9%, vomiting 4.5%, and poor appetite 4.5%. In comparison those from historical MMF 2 g/d studies included dyspepsia 3.1% to 40%, epigastralgia 10%, nausea 3.7% to 34%, and vomiting 0.6% to 10.7%. CONCLUSION: Immunosuppression with CsA, EC-MPS, and steroids maintains stable graft functions. Minimal dose reduction of EC-MPS decreases GI adverse events but without significance. EC-MPC and MMF have respective GI side effects; they can be used alternatively in patients with individual GI intolerance.     

Impact of gastrointestinal-related side effects on mycophenolate mofetil dosing and potential therapeutic strategies

In renal transplant patients receiving mycophenolate mofetil (MMF), maintaining an adequate dosing regimen has been shown to maximize short- and long-term outcomes. Gastrointestinal (GI) adverse events associated with MMF are frequent, and lead to MMF dose reduction or withdrawal in 40-50% of cases. Among MMF-treated patients experiencing GI complications, one analysis has reported MMF discontinuation to be associated with almost a threefold increase in risk of graft loss, while a dose reduction > or = 50% carried over a twofold increase in risk. If GI symptoms improve and the pre-reduction MMF dose is resumed the increased risk of graft loss may be reversed, but continuing intolerance can make this difficult to achieve. Investigation of contributing factors is important and may alleviate symptoms. Conversion to enteric-coated mycophenolate sodium (EC-MPS) may be an effective option. Two open-label studies using patient-reported outcomes data have shown a significant and clinically relevant benefit in GI-related symptom burden after conversion from MMF to EC-MPS. In conclusion, monitoring of GI complications is essential following renal transplantation, and maintaining adequate mycophenolic acid exposure should be a priority when considering treatment options.     

Enteric-Coated Mycophenolate Sodium can be Safely Administered in Maintenance Renal Transplant Patients: Results of a 1-Year Study

With the objective of enhancing upper gastrointestinal (GI) tolerability, enteric-coated mycophenolate sodium (EC-MPS, myfortic, Novartis Pharma AG, Basel, Switzerland) has been developed. This double-blinded, 12-month study investigated whether renal transplant patients taking mycophenolate mofetil (MMF) can be safely converted to EC-MPS. Stable kidney transplant patients were randomized to receive EC-MPS (720 mg b.i.d.; n=159) or continue receiving MMF (1000 mg b.i.d.; n=163). The incidence of GI adverse events (AEs) was similar at 3 months (primary endpoint: EC-MPS 26.4%; MMF 20.9%; p=NS) and at 12 months (EC-MPS 29.6%; MMF 24.5%; p=NS). The increase from baseline in mean GI AE severity score, adjusted for duration, tended to be lower in EC-MPS patients (3 months: 0.15 vs. 0.20; 12 months: 0.23 vs. 0.47; p=NS). Neutropenia (<1500 cells/mm3) within the first 3 months (coprimary endpoint) was low in both groups (EC-MPS 0.6%; MMF 3.1%; p=NS). Although the overall incidence of infections was similar, the number of serious infections was significantly lower in EC-MPS patients (8.8% vs. 16.0%; p<0.05). Similar rates of efficacy failure (EC-MPS 2.5%; MMF 6.1%; p=NS), biopsy-proven acute rejection (EC-MPS 1.3%; MMF 3.1%; p=NS) and biopsy-proven chronic rejection (EC-MPS 3.8%; MMF 4.9%; p=NS) were observed in both groups. In conclusion, renal maintenance patients can be converted from MMF to EC-MPS without compromising the safety and efficacy profile associated with MMF.     

Switching From Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium in Liver Transplant Patients With Gastrointestinal Complications

Objective

Our aim was to safely and effectively reduce adverse gastrointestinal (GI) events resulting from the use of mycophenolate mofetil (MMF) in liver transplant patients by switching to enteric-coated mycophenolate sodium (EC-MPS).

Patients and Methods

We studied 19 patients on maintenance therapy presenting with GI intolerance to MMF whose therapy was switched to EC-MPS. The variables recorded were: calcineurin inhibitor (CNI) dose levels, MMF/EC-MPS dose levels, lipid profile, hematology, renal and hepatic function markers, and rejection episodes. These variables were recorded at the visit prior to the day of conversion, on the day of conversion, and 1, 3, 6, and 9 months thereafter.

Results

Of the 19 patients, 16 were men (mean age, 56.6 ± 15.9 years) and 3 were women (58.3 ± 12.1 years). While 31.6% were on MMF monotherapy, 52.6% were on combined therapy with tacrolimus and 15.8% with cyclosporine. On the day of conversion, 21% were not on MMF, 36.8% were on 1000 mg/d, 26.3% were on 1500 mg/d, 5.3% were on 750 mg/d, and 10.6% were on 500 mg/d. The starting daily doses of EC-MPS were: 360 mg (26.3%), 720 mg (31.6%), 540 mg (26.3%), 1080 mg (10.5%), and 1440 mg (5.3%). GI complications were significantly reduced from the first month postconversion (P < .01), as 57.2% of patients did not display any symptoms; however, at 9 months, this incidence rose by 12% relative to month 1 (P < .05). There were no changes in the other variables and there were no reported rejection episodes. Treatment was suspended in 2 patients due to dyspnea and nervousness.

Conclusion

In liver transplant patients with GI complications from chronic MMF use, the use of EC-MPS was safe and efficacious, as it significantly reduced their incidence.     

Enteric-Coated Mycophenolate Sodium is Therapeutically Equivalent to Mycophenolate Mofetil in de novo Renal Transplant Patients

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side-effects. An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC-MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12-month, double-blind study. Efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC-MPS 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC-MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC-MPS and 9.8% with MMF (p=ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC-MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p=ns). Enteric-coated-MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.     

Mycophenolic acid in kidney transplant patients with diabetes mellitus: does the formulation matter?

Diabetes mellitus is frequent in kidney transplant recipients and is commonly associated with gastrointestinal (GI) complications. Delayed gastric emptying affects 30% to 50% of patients with type 1 or 2 diabetes and can influence oral drug absorption. Time-to-peak concentration of mycophenolic acid (MPA) from mycophenolate mofetil (MMF) is longer in diabetic kidney transplant patients than patients without diabetes. By retaining gut contents in the stomach for longer, this could increase local GI toxicity in diabetic recipients due to an extended duration of exposure to MPA in the stomach. The enteric-coated mycophenolate sodium (EC-MPS) formulation delays the release of MPA until pH is higher than 5.5, such that absorption takes place more distally compared with MMF. Patient-reported outcomes data have been used to assess the effect of conversion to EC-MPS in maintenance kidney transplant patients with diabetes who were experiencing MMF-related GI symptoms. Results indicated that conversion leads to improved GI symptom burden despite higher MPA exposure under the EC-MPS regimen. Improved GI tolerance using EC-MPS has permitted maintenance of optimal MPA exposure in nondiabetic populations. Comparative trials to evaluate the GI symptom burden and maximum achieved MPA dosing using the EC-MPS and MMF formulations in de novo and maintenance diabetic kidney transplant recipients are merited.     

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.