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.     

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.     

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.     

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.     

Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium

Enteric-coated mycophenolate sodium (EC-MPS) (myfortic) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady-state pharmacokinetic study in stable renal transplant patients receiving EC-MPS demonstrated increased MPA exposure of 19% higher, MPA C(max,ss) 19% lower and MPA C(min,ss) approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug-related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Safety and efficacy after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium: results of a 1-year extension study

Enteric-coated mycophenolate sodium (EC-MPS) is an enteric-coated formulation of mycophenolic acid. A 12-month, multicenter, double-blind, randomized clinical study demonstrated that converting maintenance renal transplant patients from mycophenolate mofetil (MMF) to EC-MPS is safe and does not affect efficacy. In an open-label study extension, 130 patients initially randomized to MMF were converted to EC-MPS (newly exposed); 130 initially randomized to EC-MPS continued on EC-MPS (EC-MPS long-term). A composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, or death occurred in 3 (2.3%) newly exposed and 2 (1.5%) EC-MPS long-term patients during the extension phase. One patient died and one lost his graft. BPAR occurred in 3 (2.3%) newly exposed patients and 1 (0.8%) EC-MPS long-term patient. During the first 12 months of the extension phase, incidence and type of adverse events was similar in both groups and comparable to that seen in the core study. Nine cases of malignancy were reported, mainly nonmelanoma skin cancers. EC-MPS dose adjustments for adverse events were required in <12% of patients. At the end of the 12-month extension, 58 (44.6%) and 64 (49.2%) newly exposed and EC-MPS long-term patients, respectively, had reported at least one gastrointestinal adverse event. Mean serum creatinine remained stable at the 12-month visit of the extension study (137 micromol/L in the newly exposed and 142 micromol/L in the EC-MPS long-term groups). The results of this study demonstrate the long-term safety of EC-MPS and reconfirm the safety of converting MMF maintenance renal transplant patients to EC-MPS.     

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.     

Mycophenolates in transplantation

The discovery of mycophenolic acid (MPA) as a potent immunosuppressant, able to inhibit B- and T-cell proliferation by blocking production of guanosine nucleotides required for DNA synthesis, allowed its potential in the field of transplantation to be realized. Mycophenolate mofetil (MMF), an MPA prodrug, has been shown to be an effective immunosuppressant in transplant therapy. Clinical trials in renal, heart, and liver transplant recipients have demonstrated that, in combination with cyclosporine and steroids, MMF therapy can reduce the incidence and severity of acute rejection episodes and improve graft and patient survival as well as graft function. Although MMF is generally well tolerated, optimal therapy may be limited by associated side effects, in particular gastrointestinal (GI) toxicity, which may occur in over 40% of patients. Dose changes resulting from GI side effects may potentially lead to sub-therapeutic dosing and impaired clinical outcomes. An enteric-coated formulation delivering MPA - enteric-coated mycophenolate sodium (EC-MPS) has been developed to improve MPA-related upper GI adverse events. EC-MPS delays the release of MPA, consistent with a functional enteric-coating. Recent clinical trials have demonstrated that EC-MPS is as effective and safe as MMF in both de novo and maintenance renal transplant patients.     

Long‐term dosing patterns of enteric‐coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation

MORE was a four‐yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric‐coated mycophenolate sodium (EC‐MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC‐MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy‐proven acute rejection, graft loss or death to be similar for EC‐MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC‐MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC‐MPS and MMF cohorts during follow‐up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC‐MPS vs. MMF, without an increase in adverse events.     

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 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.     

Superior Efficacy of Enteric-coated Mycophenolate vs Mycophenolate Mofetil in De Novo Transplant Recipients: Pooled Analysis

Dose reduction and discontinuation of mycophenolate mofetil (MMF) therapy because of gastrointestinal complications has been associated with increased risk of acute rejection episodes and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) delays release of mycophenolic acid (MPA), and was designed to reduce MPA-related gastrointestinal adverse events. Data comparing the efficacy of EC-MPS vs MMF in de novo renal transplant (RTx) recipients from large prospective studies are limited. Therefore, a pooled data analysis was performed based on 1891 de novo RTx recipients receiving EC-MPS (n = 1289) or MMF (n = 602) plus cyclosporine and steroid therapy in 4 prospective multicenter studies with similar entry criteria. In all trials, the initial dose of EC-MPS was 1440 mg/d, and of MMF was 2000 mg/d; both dosages deliver equimolar amounts of MPA. Induction therapy was permitted in 2 studies per center practice. Multivariate logistic regression analysis was performed, adjusting other potential explanatory variables including recipient age, sex, and race/ethnicity; induction therapy; and diabetes mellitus at baseline. In addition, propensity scores were used to explain potential bias. Mean (SD) MPA dose (EC-MPS dosage was converted to MMF equivalent) during months 0 to 12 was similar: EC-MPS, 1820 (370) mg/d, vs MMF, 1860 (290) mg/d. However, at univariate and multivariate analyses, the rates of treatment failure, biopsy-proved acute rejection episodes, and graft loss were significantly lower with EC-MPS compared with MMF at month 12. In conclusion, this pooled analysis documents a substantial improvement in efficacy in de novo RTx recipients receiving EC-MPS vs MMF with concomitant cyclosporine and steroid therapy.