Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients presenting gastrointestinal disorders: a pilot study.

Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of this prospective study was to evaluate the effect of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in liver transplant patients presenting GI side-effects Since January 2003, stable liver transplant patients receiving MMF and presenting GI disorders, without evidence of other origin than MMF were enrolled. Conversion was performed without a washout period at an equimolar daily dosage. Thirty-six patients were included after a median delay of 45 months after liver transplantation (LT) (16 women and 20 men, median age of 47 years). Diarrhoea was the main clinical symptom (n = 28, 77.7%). At the time of inclusion, patients were treated with MMF since 18 months (range 3-28) and GI disorders were known for 9 months (range 3-12). After a median follow-up of 12 months after conversion, GI disorders were resolved in 20 patients (55%), improved in 6 patients (17%) and not modified or worsened in 10 patients (28%). Our results strongly suggest that conversion from MMF to EC-MPS in liver transplant patients can improve gastrointestinal disorders in a majority of the patients, and therefore might be considered as the best therapeutic option.     

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 maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes

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.     

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.     

Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil

Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is routinely used as an adjunct immunosuppressant therapy in renal transplantation. Although highly effective, MMF therapy is associated with significant gastrointestinal adverse effects. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering MPA. The enteric coat dissolves at pH > 5 allowing for MPA delivery in the small intestine. A single-center, open-label, randomized, three-way crossover study of 24 stable Caucasian renal transplant patients receiving cyclosporine-based immunosuppression, compared the relative bioavailability of two EC-MPS doses (640 and 720 mg) with MMF (1000 mg). Both EC-MPS doses delivered bioequivalent mean MPA exposure (AUC(0-infinity)) compared with 1000 mg MMF: 60.7 microg h/mL for 640 mg EC-MPS, 66.5 microg h/mL for 720 mg EC-MPS, and 63.7 microg h/mL for 1000 mg MMF. Median t(max) was significantly delayed for both EC-MPS doses compared with MMF (2.0 h vs. 0.75 h, respectively; p < 0.01), consistent with a functional enteric coating of EC-MPS. Furthermore, both EC-MPS doses were bioequivalent to 1000 mg MMF for AUC and C(max) for mycophenolic acid glucuronide. All three treatments were well tolerated. The EC-MPS 720 mg dose most closely approximated the MPA exposure of 1000 mg MMF and was selected for subsequent phase III studies.     

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.     

Enteric-coated mycophenolate sodium immunosuppression in renal transplant patients: efficacy and dosing

Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) formulation, has improved both short- and long-term outcomes following renal transplantation, but is often associated with gastrointestinal (GI) complications that can lead to dose reduction or discontinuation, potentially jeopardizing patient outcomes. Enteric-coated mycophenolate sodium (EC-MPS) delivers equivalent MPA exposure to MMF and offers the potential to reduce GI burden (while maintaining patient safety). Here we review the efficacy of EC-MPS compared with MMF in renal transplant patients in terms of biopsy-proven acute rejection and graft loss, and examine the use of EC-MPS in newer regimens such as intensified dosing and calcineurin inhibitor minimization.     

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.     

Mycophenolic acid metabolite profile in renal transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an effective immunosuppressive treatment in renal transplant recipients but is known to have gastrointestinal side effects. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) is a new formulation for delivering MPA. This open-label, two-period, cross-over study was carried out to characterize the time course of MPA and its metabolites, mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucuronide (AcMPAG) in stable renal transplant patients (n = 40) after 28-day chronic dosing with EC-MPS (720 mg bid) or MMF (1000 mg bid). The relative abundance and exposure of all three compounds was also assessed. EC-MPS demonstrated the typical pharmacokinetic profile of an enteric-coated formulation with a delayed release of MPA compared with MMF (Tmax 2.5 versus 1.0 hours, respectively). Consistent with a similar disposition of MPA, both EC-MPS and MMF treatments resulted in the same ratio of MPAG to MPA exposure, 23:1. Furthermore, comparison of the AUC of MPAG and AcMPAG for both treatments indicated that steady state MPAG exposure was 75 to 90 times that of AcMPAG, confirming MPAG as the predominant metabolite of MPA. AcMPAG has been identified as a possible active metabolite of MPA; the present study indicates that AcMPAG may contribute around 14% of the exposure to active drug after administration of MPA. Both EC-MPS and MMF treatments were well tolerated over the 1-month period of chronic treatment. In summary, consistent with its enteric-coated design, EC-MPS delays delivery of MPA, but results in similar exposure to that provided by MMF.     

Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.     

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.     

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.     

Pharmacokinetic and Pharmacodynamic Comparison of Enteric-Coated Mycophenolate Sodium and Mycophenolate Mofetil in Maintenance Renal Transplant Patients

The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5'-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.d. participating in a double-blind, multicenter study, were randomized to receive EC-MPS (720 mg b.i.d.) or continue receiving MMF (1000 mg b.i.d.) for 12 months. Thereafter, all patients (n = 18) received 720 mg EC-MPS b.i.d. Area under the plasma mycophenolic acid (MPA) concentration-time curve with EC-MPS (57.4 +/- 15.0 microg h/mL) fulfilled bioequivalence criteria (geometric mean 0.98 (90% CI: 0.87-1.11) compared to MMF (58.4 +/- 14.1 microg h/mL). Consistent with the delayed release characteristics of EC-MPS, peak MPA concentration (geometric mean 0.89; 90% CI: 0.70-1.13) occurred approximately 0.5 h later (p < 0.05) and predose MPA levels (geometric mean 2.10; 90% CI: 1.51-2.91) were higher and more variable, not fulfilling bioequivalence criteria. IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree (approximately 85%) by both formulations. The calculated value for 50% IMPDH inhibition was identical for both drugs. In conclusion, equimolar doses of EC-MPS and MMF produce equivalent MPA exposure, while the delayed release formulation of EC-MPS exhibits more variable predose levels and T(max). Overall, IMPDH activity reflected MPA pharmacokinetics.     

Safety assessment of the conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in stable renal transplant recipients

The immunosuppressant mycophenolate mofetil (MMF; CellCept) has greatly improved transplant recipients' clinical outcomes, but its efficacy may be limited by dose adjustments due to adverse events (AEs). An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic), designed to improve gastrointestinal tolerability is now available. This Latin-American, prospective, multicenter, open-label, 6-month trial assessed the safety and tolerability of converting renal transplant recipients from MMF to EC-MPS. In total, 237 renal transplant recipients (stable > or = 3 months' posttransplant) receiving MMF (< or =1000 mg b.i.d.) were enrolled. Adults (n = 218) were converted to EC-MPS 720 mg b.i.d. (equimolar to MMF 1000 mg b.i.d.) even if they were initially receiving <1000 mg MMF b.i.d. (ie, 47 adults received a higher than equimolar dose of EC-MPS). Children (n = 19) were converted to EC-MPS 450 or 432 mg/m2 b.i.d. Patients also received cyclosporine microemulsion (Neoral) and corticosteroids. There were three acute rejections and no graft failures. The incidence of AEs was 59.9% (in those receiving a higher than equimolar EC-MPS dose it was 57.4%). In all, 22% of patients had gastrointestinal AEs, 37% had infections, and 4.8% had hematological AEs. Only 24 patients (10%) had an AE-related dose reduction. Seven of these patients had received higher than equimolar doses of EC-MPS. Patients can be safely converted from different doses of MMF to a standard dose of EC-MPS. The requirement for EC-MPS dose reduction to manage AEs was relatively low. Use of EC-MPS is a valid alternative for renal transplant recipients receiving maintenance MMF treatment.     

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.     

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 Reduces Gastrointestinal Symptoms in Renal Transplant Patients

A main cause for gastrointestinal (GI) complications in graft recipients is the routinely administered inosine monophosphate dehydrogenase inhibitor mycophenolic acid (MPA). MPA is available in two formulations, the prodrug mycophenolate mofetil (MMF) and the enteric-coated sodium salt (EC-MPS). Clinical results point to a better GI tolerability of EC-MPS as compared to MMF. We performed an open surveillance study in 397 organ graft recipients to investigate the clinical tolerability of EC-MPS in renal graft recipients who were converted from MMF to EC-MPS (maintenance) or who received EC-MPS as a new component of their immunsuppressive regimen (de novo). Physicians recorded GI symptoms (nausea, emesis, anorexia, diarrhea, abdominal cramps) at the start of EC-MPS treatment (visit 1) and at the next two visits in the clinic (visits 2 and 3); general tolerability (very good/good/moderate/poor) was assessed at visit 2 and 3. Two hundred seventy-five patients were on maintenance treatment with MMF and were converted to equimolar doses of EC-MPS, and 122 patients received EC-MPS de novo. The mean time since transplantation was 4.2 ± 4.4 years. Median time until visit 2 was 28 days and until visit 3, 65 days. In 63.0% of patients, tolerability was rated as very good at visit 2 and in 64.7% at visit 3. Most patients who had suffered from GI complications during preceding MMF treatment reported improvement or total disappearance of their symptoms after conversion to EC-MPS. In conclusion, EC-MPS is a useful means to reduce GI complications in MPA-treated patients.     

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.     

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.