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Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF), two prodrugs of mycophenolic acid (MPA), have been used in immunosuppressive regimens. After being taken orally, both of them transform to MPA to achieve immune suppression effects; however, the main site of absorption and metabolism of EC-MPS is different from that of MMF in vivo. Therefore, combined application with related drugs may result in different MPA levels and have different clinical effects in kidney transplant recipients.To evaluate the efficacy of EC-MPS compared with MMF in Chinese renal transplant patients comedicated with a proton pump inhibitor (PPI).Our subjects were 88 patients who received renal transplants at the 309th Hospital of the Chinese PLA from May 2010 to April 2013. These were made up of two groups including 27 patients with EC-MPS and 61 with MMF. The immunosuppression regimen was EC-MPS/MMF + cyclosporine/tacrolimus + steroid hormone, comedicated with a PPI (omeprazole). The patients' levels of exposure of MPA within 1 week after operation were monitored. Clinical indicators such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine hemoglobin, leucocytes, and neutrophils, as well as clinical adverse drug reactions and drug conversion were analyzed retrospectively.The kidney function of patients recovered to normal in both the EC-MPS and MMF groups. The mean concentration to peak (Cmax), the mean half-life (t1/2), and the area under the concentration-time curve (AUC0-12) of MPA in the EC-MPS group were higher than those in the MMF group (P.05). This indicated that the pharmacokinetic parameters for MPA when EC-MPS is co-administered with a PPI in kidney transplant patients in China is better than for comedication with MMF and a PPI. The MMF group had a higher incidence of drug withdrawal because of higher infection rates, leucocyte decrease, and more gastrointestinal side effects than the EC-MPS group (P.05). No significant differences in the clinical effect on kidney transplant recipients were observed in the limited observation time.

Introduction: To discuss the significance of the recent observational case series from the Swiss Toxicological Information Centre (STIC). Mycophenolic acid (MPA) and its prodrug mycophenolate mofetil are immunosuppressive agents that are frequently prescribed in renal transplant recipients, and their safety profiles must be established. Areas covered: This case series and systemic literature analysis consists of 15 cases of MPA overdose from the STIC and a systemic analysis of the literature over the past 18 years. This study focuses on acute overdosing, the effects of which are presumably mild. In contrast, the effects of long-term overdosing may be much more severe. Substantial underreporting is likely. The pharmacokinetic monitoring of MPA is rarely performed, which is both striking and does not coincide with findings in academic literature. The scant data on pharmacokinetic monitoring presented demonstrated that MPA has a short terminal half-life, which suggests that decontamination and activated charcoal treatment in acute overdose may not be necessary. Expert opinion: The case series and systematic literature analysis of acute mycophenolate overdose represent an important contribution toward increasing the safety of MPA therapy. © 2014 Informa UK, Ltd.

Summary Aims There are few pharmacokinetic data for enteric-coated mycophenolate sodium (EC-MPS) in Chinese kidney transplant recipients. Previously, we demonstrated that patients with 540 mg EC-MPS reached target exposure on day 4 after transplantation. The aim of this study was further to confirm that mycophenolic acid (MPA) delivery with a daily total dose 1080 mg EC-MPS is adequate during the early-phase posttransplantation and preliminarily assess the pharmacokinetics after a single dose and multiple doses of EC-MPS in Chinese live-donor kidney transplant recipients. Methods Twelve patients (eight men and four women, mean age 41.3 ± 6.78 years) treated with EC-MPS, cyclosporine and corticosteroids were included in this study. Patients received a single oral dose of EC-MPS 540 mg, then 540 mg twice daily. MPA concentrations were measured by high-performance liquid chromatography. Twelve-hour pharmacokinetic profiles were obtained after the single oral dose and multiple doses on day 4 postoperation. The pharmacokinetic parameters were compared between a single dose and multiple doses. By using multiple stepwise regression analysis, we obtained two predictive equations of MPA systemic exposure. Bland–Altman analysis was developed to test agreement between the observed MPA area under the concentration–time curve (AUC) and the predicted MPA AUC. Results The mean (range) MPA AUC was 42 ± 14.67 (29.29–75.95) mg/l h after the first dose, and 44.72 ± 14.57 (32.06–80.79) mg/l h on day 4 after operation. MPA exposure provided by a single dose and multiple doses were similar (p > 0.05). The best equations obtained were the following: 20.003 + 1.181C6 h + 7.22C8 h (r = 0.936) and 17.023 + 3.11C1 h + 1.245 + 4.988C8 h (r = 0.964). These equation models showed an optimal agreement between the observed MPA AUC and the predicted MPA AUC. Conclusions Lower dosing of EC-MPS, compared with the standard dose (720 mg twice daily), may provide enough MPA exposure for Chinese live-donor kidney transplant patients on day 4. Given that the MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications, and the optimum dose range of EC-MPS for patients in all ranges of body weight should also be determined.

Summary Aims To investigate the pharmacokinetics of enteric-coated mycophenolate sodium (EC-MPS) and the clinical outcome in kidney transplant recipients in the early post-transplantation phase. Then explain which regimen is more suitable for Chinese renal transplant recipients. Methodology In total, 60 de novo kidney transplant recipients treated with tacrolimus and steroids were randomised to receive EC-MPS at standard dose (SD; 1440 mg/day; n = 28) or low dose (LD; 1080 mg/day; n = 32). Efficacy parameters, safety and tolerability were assessed over a 6-month study period. Full mycophenolic acid (MPA) areas under the curve (AUCs) were completed on days 3 and 5, whereas a three-point limited sampling strategy (LSS) was utilised for MPA AUC assessments at 2 weeks and months 1, 3 and 6 (the LSS for three-time-point MPA AUC 0–12 h (mg h/l) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h; r2 = 0.8670. Results The mean AUC levels at day 3 and day 5 in the SD group were significantly higher than in the LD group (57.4 mg·h/l vs. 38.2 mg·h/l and 59.3 mg·h/l vs. 44.8 mg·h/l, respectively, p

Summary Objective To observe the different concentrations of mycophenolic acid (MPA) during the early post-transplant phase for various combinations of cyclosporine A (CsA) and tacrolimus (Tac) with enteric-coated mycophenolate sodium (EC-MPS). Method A total of 42 Chinese adults receiving live related donor kidney transplants were studied. All received a triple immunosuppressive regimen of EC-MPS, CsA/Tac and corticosteroids and were divided randomly into CsA (n = 21) and Tac (n = 21) combination groups. The dosage of EC-MPS was the same (1440 mg/day) in the two groups. The MPA concentration was evaluated with an enzyme-multiplied immunoassay technique (EMIT) and the pharmacokinetic characteristics were investigated in both groups. Results The mean maximum plasma concentrations (Cmax) of MPA in the CsA and Tac groups were 11.365 ± 9.522 and 9.748 ± 7.523 μg/ml, respectively (p = 0.137). The maximum times to Cmax (Tmax) were 2.54 ± 1.53 and 2.67 ± 1.08 h, respectively (p = 0.341). The mean MPA 12-h areas under the curve (MPA-AUC0–12 h) were 59.463 ± 16.252 and 77.535 ± 33.615 μg h/ml (p = 0.003) and the mean residence times (MRT) were 3.71 ± 0.829 and 3.928 ± 0.923 h (p = 0.038). Conclusion Combined with the same EC-MPS dosage (1440 mg/day), the MPA-AUC0–12 of the Tac group was higher than that of the CsA group, and the Tac group had a longer MRT after kidney transplantation. Our data indicate that the concentration of MPA should be monitored in clinical therapy when EC-MPS is combined with different calcineurin inhibitors to reduce acute allograft rejection and avoid adverse events.

BACKGROUND Patients with a simultaneous pancreas-kidney transplant (SPKT), especially those with gastroparesis, often have gastro-intestinal (GI) disorders that can modify immunosuppressant pharmacokinetics. We compared the MPA 12-hours area under the curve (AUC(0-12)) in SKPT patients with severe gastroparesis receiving mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). MATERIAL/METHODS Fifteen SKPT patients having a severe gastroparesis were switched, at 182 (69-1523) days post-transplantation, from MMF to EC-MPS because of GI disorders. MPA AUC(0-12) values were obtained before and after the switch, ie, under MMF (500 mg b.i.d.) at 169 (51-1522) days post-transplantation and EC-MPS (360 mg b.i.d.) at 102 (26-355) days after the switch. RESULTS Mean MPA AUC(0-12) h did not differ significantly under MMF and EC-MPS, ie, 40.13±14 and 38.24±15.5 mg*h/L, respectively. Trough and maximal MPA concentrations were similar with both MPA formulations. Although all patients had GI disorders under MMF (100%), only 3 had persistent GI disorders under EC-MPS (20%) (p

Aim Mycophenolate is an immunosuppressive agent which has been used in systemic lupus erythematosus (SLE) patients who have failed conventional therapy. However, the use of mycophenolate sodium in extra-renal SLE involvement has yet to be established. This study aimed to assess the efficacy of mycophenolate sodium in extra-renal SLE. Methods A total of 14 SLE patients without renal involvement were randomized either to receive mycophenolate sodium or other immunosuppressive agents. Patients were assessed monthly from baseline until week 16. Assessment parameters included SLE Disease Activity Index (SLEDAI) score, other organ-specific parameters and immunological parameters, including anti-double stranded DNA and C3. Steroid-sparing effect of mycophenolate sodium was also evaluated. Results Mycophenolate sodium produced a significant reduction in SLEDAI scores (P

A simple stability-indicating isocratic RP-HPLC method was developed and validated for the determination of mycophenolate sodium and its alkali degradation product. Forced degradation of the drug was carried out under thermolytic, photolytic, acid/base hydrolytic, and oxidative stress conditions. Alkali degradation product DP1 was isolated, and separation of stress degradation products was achieved on a Symmetry C18 (250 × 4.6 mm × 5.0 μm) column using the mobile phase methanol–acetate buffer adjusted with acetic acid to pH 6.0 (76 + 24, v/v) at a 0.55 mL/min flow rate and 50°C. Data were integrated at the detection wavelength of 251 nm. The method validation characteristics included accuracy, precision, linearity, range, specificity, and sensitivity per International Conference on Harmonization guidelines. Robustness testing was conducted to evaluate the effect of minor changes in the chromatographic conditions and to establish appropriate system suitability parameters. Structural elucidation of degraded products was performed by HPLC/MS/MS. The method was used successfully for drug product analysis, dissolution study, and determination of the drug's acid, alkali, and oxidative degradation kinetics.

Background Limited mycophenolic acid (MPA) data are available comparing racial influence on mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) pharmacokinetics. Methods Intrapatient MPA pharmacokinetics of MMF versus EC-MPS were compared in 13 male African American (AA) and 14 Caucasian (C) renal transplant recipients (RTRs). RTRs were switched to equivalent doses of the alternate formulation for at least 10 days prior to the second study. Mycophenolic acid clearance and dose-normalized area under the concentration-time curve(0-12) (AUC*) were determined. Mixed model statistics evaluated the main effects of race, drug formulation, and interaction of race and drug formulation (R × D) with albumin, cyclosporine trough, renal function, and diabetes and enterhepatic recirculation. Results Significant R × D was identified for MPA AUC* for EC-MPS (AA, 0.056 ± 0.029 [mg·h/L]/mg; C, 0.080 ± 0.044 [mg·h/L]/mg) compared with MMF (AA, 0.053 ± 0.019 [mg·h/L]/mg; C, 0.060 ± 0.025 [mg·h/L]/mg), P = .022. Significant R × D was identified with albumin in the model for MPA clearance for MMF (AA, 21.7 ± 8.9 L/h; C, 20.5 ± 10.8 L/h) compared with EC-MPS (AA, 22.2 ± 10.1 L/h; C, 16.2 ± 9.1 L/h), P = .032. Conclusions Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion.

The most common immunosuppressive regimens after renal transplantation include calcineurin inhibitors (CNI). However, due to renal toxicity long-term graft survival does not seem to be positively affected by CNIs.In the present study, we investigated 17 patients, in which the CNI immunosuppression was converted to a CNI-free, mycophenolate sodium (MPS) regimen. Conversion was performed due to progressive impairment of the graft function from suspected CNI toxicity. We retrospectively analyzed graft function as well as toxicity and surrogate markers for 4 years before and 4 years after conversion using a repeated-measures mixed model data analysis and/or a paired sample t-test.The mean time point of therapy conversion was 11.2 ± 4.6 years after transplantation. Within 1 month of CNI discontinuation, allograft function improved significantly, remaining at a significant level for 2 years. The estimated glomerular filtration rate increased from 43.4 ± 14.8 to a maximum of 55.7 ± 21.7 mL/min at 1 year after conversion (P = .0027). After 4 years, the end of the observation period, renal function was similar to the baseline. There were no significant side effects.These data suggested that, when chronic CNI-toxicity is suspected, renal allograft recipients may benefit from CNI withdrawal in favor of a MPS-including immunosuppressive regimen.

Acute graft-versus host disease (aGVHD) is a multi-step process occurring after allogeneic hematopoietic stem cell transplantation (allo-SCT), characterized by (I) tissue damage to the recipient by pretransplant preparative chemotherapy, (II) donor T cell activation in response to host alloantigens and (III) cytokine secretion by donor T cells (1). Notwithstanding continued improvements in outcomes after allo-SCT (2), aGVHD and chronic graft-versus-host disease (cGVHD) continue to be major causes of post-transplant morbidity, nonrelapse mortality, and health-related quality of life (3). Despite the routine use of prophylactic therapies, incidence rates of aGVHD and cGVHD reach 40% to 50% and 30% to 70% (3), respectively, even among matched sibling donor recipients of allo-SCT. This article is protected by copyright. All rights reserved.

Aim Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. Methods Twelve-month, prospective, randomized, open-label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. Results There was no significant difference in mean Cockcroft-Gault CrCl (creatinine clearance) (60.2 ± 17.6 mL/min per 1.73 m2 vs 63.2 ± 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. Conclusion This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.

Aim Mycophenolate mofetil has proven efficacy in the prophylaxis of acute rejection in solid organ transplantation; however, gastrointestinal intolerance can risk this efficacy because of associated dose adjustments and discontinued treatment. Enteric-coated mycophenolate sodium has demonstrated improved gastrointestinal tolerability, but the data in Asian subjects are scarce. Methods This was a Phase-IIIb, open-label, single-arm, multicentre, prospective 6-month study which investigated safety and graft function in stable maintenance renal transplant recipients of Asian origin, after switching from mycophenolate mofetil to enteric-coated mycophenolate sodium at least 3 months after transplantation. Primary end-points included renal allograft function and safety parameters. Results The study recruited patients from 16 centres in Asian countries. The intention-to-treat and safety populations both included 122 patients. Graft function remained stable over the course of the study as measured by creatinine clearance and glomerular filtration rate. At 6 months the incidence of any gastrointestinal adverse events was 20.5% (n = 25), none of which required dose adjustments. There were only three cases of biopsy proven acute rejection with no reports of graft loss or death. Conclusion This study demonstrated that enteric-coated mycophenolate sodium is a safe and effective alternative to mycophenolate mofetil in Asian kidney transplant recipients.

Mycophenolic acid (MPA) is an immunosuppression agent for the prophylaxis of organ rejection in patients receiving allogeneic transplants. The drug is administered based in 2 formulations, mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). MPA acts by specific, reversible, uncompetitive inhibition of inosine monophosphate dehydrogenase (IMPDH) and thus blocks the proliferation of both T- and B-activated lymphocytes. Therapeutic drug monitoring (TDM) constitutes an important part of immunosuppressive treatment because of the demonstrated significant intraindividual and interindividual variability of its pharmacokinetic behavior. TDM is required to optimize immunosuppressive efficacy. We present the analytical validation of a homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique for determination of MPA in human plasma, and compare with a homogeneous enzyme immunoassay technique (EMIT; reference method), both methods adapted on a Dimension analyzer (Siemens). We examined 50 human plasma samples from kidney transplant recipients treated with MMF or EC-MPA, which were analyzed simultaneously by both methods. The interassay precision was 5.95% at a concentration of 1.0 μg/mL, 3.47% at 7.5 μg/mL, and 3.75% at 12.0 μg/mL. The bias of PETINIA-MPA for each of the 3 quality control sample was

In solid organ transplant patients, it is important to maintain a fine balance between preventing rejection and reducing adverse effects. Several immunosuppressive agents such tacrolimus, cyclosporine, sirolimus and everolimus require therapeutic drug monitoring. The study of germline variation of the genome has opened novel opportunities to individualize therapy. Among the currently available immunosuppressive agents, cyclosporine, tacrolimus and mycophenolic acid are in vitro substrates of the UGT1A and 2B families of glucuronidation enzymes. Mycophenolic acid, either given as mycophenolate mofetil or mycophenolate sodium, is the most frequently used antiproliferative immunosuppressant. Mycophenolic acid is a prodrug which is rapidly de-esterified in the gut wall, blood, liver and tissue to the active moiety, mycophenolic acid (MPA). MPA undergoes significant hepatic metabolism to several metabolites. The 7-hydroxyglucuronide MPA is the major metabolite and is inactive. This paper reviews the current status of the genetic associations between germline UGT variants and the pharmacokinetics and pharmacodynamics of mycophenolic acid. Our conclusive assessment of the studies conducted so far is that these germline markers are not ready to be used in the clinic to individualize mycophenolic acid dosing and improve outcome. Novel approaches are required to identify new genetic determinants of outcomes in transplantation.

Background and aim Everolimus (EVR) use in liver transplantation (OLT) has been prescribed with calcineurin inhibitors (CNIs), steroids, and monoclonal antibodies. The aim of our study was to evaluate the safety, feasibility, and impact on renal function of EVR ab initio, in combination with enteric-coated mycophenolate sodium (EC-MPS) without the use of induction treatment, steroids, or CNIs. Patients and methods We retrospective analyzed nine consecutive patients who underwent OLT at our institution. The initial dose of EVR (1.5 mg/d) was adjusted to achieve trough levels of 8 to 12 ng/mL. EC-MPS introduced at 1080 mg/d was maintained at the same dose over time. Results At a mean follow-up of 21.48 (standard deviation [SD] 1.4) months from OLT, 7/9 recipients were alive with stable graft function. The 2-year patient and graft survivals were 77%. One recipient died due to cerebral hemorrhage and one, lung failure. No clinical evidence of an acute rejection episode was observed. Mean estimated glomerular filtration rate value, according to the Modification of Diet in Renal Disease formula increased from 59.5 (SD 9.89) mL/min/1.73 m 2 at OLT to 100.2 (SD 47.5) mL/min/1.73 m 2 ( P = .03) after 12 months and 98.71 (SD 33.74) mL/min/1.73 m 2 ( P = .03) after 24 months' follow-up. Conclusion A double immunosuppression therapy with EVR and EC-MPS ab initio seemed to be efficacions and safe, representing a valid alternative to CNIs to prevent renal failure after OLT.

Background Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. Study design Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). Results The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). Conclusions : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.

Several immunosuppressive drugs are used as steroid-sparing agents in pemphigus vulgaris (PV) treatment, with the aim of reducing the cumulative dose of steroids and minimizing the side effects of long-term steroid treatment. The objective of this study is to evaluate the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) as a steroid-sparing agent in PV patients. We performed a retrospective study on PV patients who had attended our dermatology department between October 2004 and December 2010 and who had been treated with a combined therapy of systemic corticosteroids and EC-MPS. In the 16 enrolled patients, the introduction of EC-MPS allowed the tapering of systemic corticosteroids, and in 12 of these patients, complete remission was achieved in the time of observation, on average in 4.3 months. Corticosteroid withdrawal was possible in two patients, and EC-MPS was very well tolerated. No serious adverse events were recorded. EC-MPS is a valid therapeutic opportunity as a steroid-sparing agent in PV patients.

International audience; Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 ± 11.1 and 44.7 ± 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 ± 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 ± 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d.

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

Background In this prospective study we investigated the impact of the proton pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid (MPA) after oral administration of enteric-coated mycophenolate sodium (EC-MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF; CellCept) by 34% in area under the concentration–time curve (AUC). Because gastrointestinal side-effects are common after organ transplantation, we investigated the effect of PPI on MPA levels in patients receiving EC-MPS. Methods MPA plasma concentrations and inosine monophosphate dehydrogenase (IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained from 21 patients. These patients were treated with pantoprazole 40 mg once daily and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated after pantoprazole withdrawal. Results MPA concentrations and IMPDH activities did not reveal any significant difference during PPI treatment and after withdrawal. MPA AUC, MPA C max (maximal MPA concentration), the time until C max was reached (T max ) and IMPDH activity AUC all showed no significant difference. Conclusion We did not find an influence of pantoprazole on EC-MPS pharmacokinetics such as we did for MMF in our previous investigation. A further prospective, large, cross-over study is planned to support these preliminary results. Given that MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications.

International audience; UNLABELLED: This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations. SUMMARY POINTS: Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes. Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. The area under the concentration-time curve (AUC 0-12) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC 0-12, trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance b25 mL/min) to guide dosage estimation, especially because renal function changes over time after transplant, while recognizing that robust prospective studies to show the clinical advantage of measuring free MPA exposure are still required. Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure. A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal clinical outcome. Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn. Assessment of UGT1A9 single nucleotide polymorphisms (-275TNA, -2152CNT, -440CNT, -331TNC) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant. Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles.

Mycophenolate acid (MPA) therapy is associated with a decrease in acute rejection rates and excellent renal allograft survival. Unfortunately, mycophenolate mofetil (MMF) is associated with significant adverse effects (AE), which, in many cases, preclude full-dose therapy. Previously, lower MMF drug exposure was significantly associated with a greater risk of rejection. Patients who had a ≥50% dose reduction of MMF experienced a lower graft survival compared to those who tolerated full-dose MMF. Mycophenolate sodium (MPS) was designed to lessen MPA-associated AE. In this retrospective study, we studied the tolerability and long-term outcomes in renal transplant recipients (RTR) treated with MPS versus MMF. Four hundred forty-nine RTRs who received MPS or MMF for more than 3 months were classified into three groups: group 1: MMF-treated; group 2: MPS-treated; and group 3; patients who converted from MMF to MPS due to AE. Donor and recipient demographics as well as induction and maintenance immunosuppressive therapies were similar in all groups. Patient survival was not different in all groups. However, long-term graft survival was lower in patients whose dose of either MPS or MMF was reduced by ≥50%. Moreover, a ≥50% MPA dose reduction was associated with a higher rate of rejection compared to full dose (38% vs 21%, respectively, P < .01). Compared to patients treated initially with MMF, fewer MPS-treated recipients required dose reductions (65% vs 42%, respectively, P < .001). Furthermore, 38% of patients in group 3 tolerated full-dose MPS despite previous intolerance to MMF. Finally, the long-term graft survival was best in MPS-treated RTR and worst in those who converted from MMF to MPS due to AE. We conclude that MPS is better tolerated than MMF, which may explain the superior graft outcome in RTR who were treated with MPS from the onset.

Mycophenolate drug levels are decreased by co-administration of cyclosporine. However, mycophenolate levels may be associated with insufficient immunosuppression. We investigated the pharmacokinetics of 720 mg mycophenolate sodium (EC-MPS) and inosine monophosphate dehydrogenase (IMPDH) activity under co-medication with cyclosporine and steroids within the first 30 d after kidney transplantation (n = 24). Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h after the morning dose. Plasma concentrations of mycophenolic acid, its glucuronide metabolites (MPAG; AcMPAG), and free MPA were determined using validated HPLC-DAD. IMPDH activity in leukocytes was analyzed chromatographically. Only six of 24 patients had an MPA-AUC(12h) within the putative therapeutic range of 40-60 mg/L·h. MPA clearance was high with 29 L/h. fMPA-AUC(12h) (r = -0.429, p = 0.04) and MPAG-AUC(12h) correlated significantly with the glomerular filtration rate, while total MPA did not. The MPAG-AUC(12h) was about 52-fold higher than the corresponding values for MPA, whereas the AcMPAG-AUC(12h) reached about 20.4% of the respective MPA-AUC(12h.) We found significant correlations between IMPDH inhibition and MPA concentration (r = -0.665; p < 0.0001), fMPA (r = -0.446; p = 0.003), and AcMPAG (r = -0.459; p = 0.002) but not with MPAG. Only 25% of the patients attained the therapeutic range for MPA-AUC under standard EC-MPS dose during the early-phase post-transplantation. We recommend that EC-MPS should be given in higher doses (3 × 720 mg) in the early post-transplant period when co-administered with cyclosporine.

The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity.The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured.The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032).The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

In this retrospective study, we compared the outcome of renal transplanted patients who received everolimus (EVR) (C0: 8-12 ng/mL)+cyclosporine (CsA) (C2: 150-300 ng/mL)+steroids, vs those who received enteric-coated mycophenolate sodium (EC-MPS) (1,440 mg/d)+CsA (C2: 500-700 ng/mL)+steroids. Efficacy was evaluated at 5 years. We found a nonsignificant trend toward a better 5-year graft survival (81.2% vs 68.6%) and better graft function (estimated glomerular filtration rate 71.8±35.7 vs 60.0±26.2 mL/min, P=.114) in favor of the EVR group. In our experience, EVR with a very low dose of CsA was associated with a nonstatistical trend toward better renal function and graft survival compared to a standard regimen of CsA and EC-MPS.

Mycophenolic acid (MPA) therapy is a fundamental component of most post-transplant immunosuppressive regimens. Side effects, however, are common and frequently necessitate dose reductions or discontinuations.Enteric-coated mycophenolate sodium (EC-MPS) is designed to improve the gastrointestinal (GI) tolerability of MPA. This review assesses the pharmacology, efficacy and safety of EC-MPS.An understanding of the use of EC-MPS in solid organ transplantation and the key trials examining the GI impact of EC-MPS versus the immediate-release mycophenolate mofetil (MMF) formulation. The article also addresses the possible impact of proton pump inhibitor therapy, and the optimal MPA dose with different concomitant immunosuppressants.Evidence from blinded trials using standard reporting measures or patient-reported outcomes has not confirmed a significant improvement in the GI symptom burden using EC-MPS. Several open-label studies, however, have consistently shown an improvement in GI tolerability with EC-MPS, which can permit restoration of the optimal MPA dose. EC-MPS has equal efficacy and possibly a different tolerability profile to MMF, thus offering a choice to physicians and their patients, particularly those experiencing MMF-related GI symptoms, diabetic patients or those in whom an MPA dose reduction is required.

Mycophenolic acid (MPA) is an effective treatment for active lupus nephritis despite its variable efficacy in different ethnic groups. Here we tested whether pharmacokinetic monitoring may help to optimize dosing of MPA in an Asian population. Patients with biopsy-proven class III or IV lupus nephritis (ISN/RPS category) were treated with mycophenolate mofetil or enteric-coated mycophenolate sodium. One month after initiating treatment we measured plasma MPA levels in eight samples taken over a 12-h period after drug administration. The mean area under the time-dependent curve for MPA of responding patients was significantly higher than those not responding. Successful treatment was seen in patients with areas45 mg h/l. The dosage of the drug was not related to MPA pharmacokinetics. In the mycophenolate mofetil group, however, MPA-area under the curve was positively, and significantly, correlated with trough or 1 h after dose concentrations and associated with a therapeutic response. Thus, our study shows that MPA pharmacokinetics were positively correlated with therapeutic responses of mycophenolate, suggesting that controlling the concentrations may improve its therapeutic efficacy in lupus nephritis. As the absorption and pharmacokinetic peak of enteric-coated tablets is slower, it is important to take different formulations into account when determining optimal MPA concentrations.

Tedesco-Silva H, Felipe CR, Park SI, Pinheiro-Machado PG, Garcia R, Slade A, Schmouder R, Medina-Pestana JO. Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients. Clin Transplant 2010: 24: E116–E123. © 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic®) may have an impact on the variability of MPA trough (C0 h) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept®), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at −1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1–80.3) and 54.4% (40.0–86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1–72.9) and 42.8% (37.9–49.2). High MPA C0 h levels >10 μg/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)0–3 h was comparable between treatments, while MPA C0 h was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C0 h levels with both treatments.

Mycophenolic acid (MPA), the active form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is used to treat systemic lupus erythematosus (SLE). MMF and EC-MPS pharmacokinetics were examined to devise guidance for therapeutic drug monitoring (TDM) for SLE patients with normal renal function.This observational study included 21 patients receiving MMF (1000 mg twice daily) and 14 taking EC-MPS (720 mg twice daily). MPA AUC between 0 and 12 h (AUC(0-12h)), C(max), T(max), and 12-h trough concentrations (C(12h)) were determined.Means of dose-normalized MMF- or EC-MPS-MPA C(max) were 64.6 +/- 25 and 61.4 +/- 27.1 h mg/l, respectively. MPA T(max) for EC-MPS was longer and more variable than for MMF. MMF-MPA AUC(0-12h) and C(12h) were correlated (r = 0.78, p = 0.0001), but EC-MPS-MPA C(max) and single concentrations were weakly correlated. A limited-sampling strategy (LSS) combining C(max) and C(12h) gave satisfactory predictive performance to estimate MPA AUC(0-12h) after EC-MPS administration.For TDM in SLE patients with GFR60 ml/min/1.73 m(2), C(12h) after MMF ingestion could predict MPA AUC(0-12h), while an LSS around T(max) should be used for patients on EC-MPS.

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.

Dose reductions or discontinuations of mycophenolate mofetil (MMF) result in higher incidences of acute rejection and graft loss. Converting renal transplant patients experiencing MMF-related gastrointestinal (GI) side effects to equimolar enteric-coated mycophenolate sodium (EC-MPS) may relieve GI symptoms.In this prospective 12-month study, renal transplant patients maintained on suboptimal MMF doses (1500 mg/d) due to GI intolerance were converted to equimolar EC-MPS followed by incremental EC-MPS dose increases (180 mg/d) every 7 weeks to an established maximum, if well tolerated. Changes in GI symptoms were assessed by physician judgment and Gastrointestinal Symptom Rating Scale (GSRS).Twenty-five patients (mean age: 52.0 +/- 13.6 years) were converted from MMF (930.0 +/- 153.4 mg/d) to equimolar EC-MPS (669.6 +/- 110.5 mg/d) at day 0. Twenty-three of 25 patients tolerated equimolar dose conversion and one or more EC-MPS dose increments at week 28. Compared to baseline, patients received significantly more EC-MPS at week 28 and week 49 (mean dose: 1033.0 +/- 164.8 mg/d, P.0001 and 1001.7 +/- 209.0 mg/d, P.0001, respectively). Two patients dropped out by week 7 for reasons unrelated to EC-MPS. The mean serum creatinine remained stable and no clinical acute rejection episodes occurred over 12 months. Mean GSRS total score remained stable through month 12 when compared to day 0 despite increases in EC-MPS dose.In renal transplant patients receiving suboptimal MMF doses due to GI symptoms, conversion to EC-MPS enabled equimolar prescription and subsequent dose increase without increased GI intolerance.

The influence of pantoprazole 40 mg twice daily on the bioavailability of a single dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is investigated in healthy volunteers. The plasma concentrations of mycophenolic acid and of the inactive metabolite mycophenolic acid glucuronide are measured by high-performance liquid chromatography. The pharmacokinetic parameters following sole administration are similar for mycophenolate mofetil and enteric-coated mycophenolate sodium except for the time to peak concentration, which is longer in the enteric-coated mycophenolate sodium group. Concomitant treatment with pantoprazole significantly (P < .001) lowers the mycophenolic acid exposure following administration of mycophenolate mofetil. The peak concentrations drop by 57%, and area under the curve decreases from 0 to 12 hours by 27%. In contrast, pantoprazole does not change the pharmacokinetics of enteric-coated mycophenolate sodium. Given that mycophenolic acid exposure correlates with the incidence of biopsy-proven acute rejections in renal transplant recipients, these findings may have clinical implications. Administration of pantoprazole in combination with mycophenolate mofetil could possibly result in an insufficient mycophenolic acid exposure, increasing the risk of treatment failure.

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

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.

Background. Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) are well established in immunosuppressive therapy after renal transplantation. The active substance, mycophenolic acid, leads to an inhibition of inosine-monophosphate-dehydrogenase (IMPDH) activity in peripheral mononuclear cells. Therefore, we analyzed the effect of different dosing patterns of MMF and EC-MPS on IMPDH activity in stable patients after renal transplantation. Methods. IMPDH activity (pmol/s per pmol AMP) was measured in patients in the maintenance phase after renal transplantation. Besides MMF or EC-MPS, immunosuppressive therapy consisted of calcineurin inhibitor with or without steroids. We performed 260 measurements in 110 patients (82 on MMF, and 28 on EC-MPS). Results. Mean patient age range of 43 women and 67 men was 22 to 74 years. Mean serum creatinine in the MMF group was 1.7 ± 1.3 mg/dL compared to 1.48 ± 0.45 mg/dL in the EC-MPS group (P < .05). The median IMPDH activity in the EC-MPS patients was lower than in the MMF patients (10 vs 24 pmol/s pmol AMP; P < .005). This was especially pronounced in patients on 1440 mg/d EC-MPS compared with 2000 mg/d MMF (P < .001). Conclusion. Measurement of IMPDH activity in renal transplantation patients adds additional information on the degree of immunosuppression. The inhibition of IMPDH activity with EC-MPS seemed more pronounced than MMF despite formally equipotent doses.

Pranav Dalal1, Monica Grafals2, Darshika Chhabra2, Lorenzo Gallon21Department of Medicine, Mount Sinai Hospital, Chicago, USA; 2Northwestern University–Feinberg School of Medicine, Chicago, USAAbstract: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an inhibitor of inosine monophosphate dehydrogenase (IMPDH). It preferentially inhibits denovo pathway of guanosine nucleotide synthesis in T and B-lymphocytes and prevents their proliferation, thereby suppresses both cell mediated and humoral immune responses. Clinical trials in kidney transplant recipients have shown the efficacy of MMF in reducing the incidence and severity of acute rejection episodes. It also improves long term graft function as well as graft and patient survival in kidney transplant recipients. MMF is useful as a component of toxicity sparing regimens to reduce or avoid exposure of steroids or calcineurin inhibitor (CNI). Enteric-coated mycophenolate sodium (EC-MPS) can be used as an alternative immunosuppressive agent in kidney transplant recipients with efficacy and safety profile similar to MMF.Keywords: mycophenolate mofetil, kidney transplantation, acute rejection, toxicity sparing

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.

BACKGROUND: Mycophenolate mofetil (MMF) has gained acceptance as an immune modulatory agent in the treatment of autoimmune disorders such as uveitis. It represented a major advance, although optimal use may be limited, in particular, by gastrointestinal (GI) side effects in up to 50 % patients. This prospective study was undertaken to evaluate the effect of conversion from mycophenolate mofetil (MMF) to an enteric-coated mycophenolate sodium (EC-MPS). PATIENTS AND METHODS: Within a cohort of 143 patients treated with MMF we prospectively followed 19 inidviduals who developed gastrointestinal side effects. Because of limited treatment alternatives, conversion to an enteric-coated mycophenolate sodium (EC-MPS) was undertaken. A standardised questionnaire (GSRS) was completed by each patient regarding GI adverse events, at predefined intervals during the study. RESULTS: The spectrum of underlying disorders included uveitis (n = 16) and ocular cicatricial pemphigoid (n = 3) that were initially treated with MMF (1000 mg BID). All patients could be kept on EC-MPS treatment and followed with a mean follow-up of 44 weeks (median ± 12). The maximum of scores on GSRS was reached at baseline (conversion to EC-MPS) in all but 3 patients. However, GSRS scores improved significantly between baseline and visit 4 (3 months) and remained stable further on (p < 0.03). In all but one (uveitis) patient the underlying disorders were under control demonstrating the similar efficacies of MMF and EC-MPS teatments. CONCLUSION: The use of EC-MPS appears to be a valid treatment option in ocular autoimmune disorders. In particular. patients with gastrointestinal problems may profit from a significantly reduced frequency of adverse events.

Background and objectives: The introduction of mycophenolate mofetil has improved graft survival after organ transplantation; however, its use may be limited by important adverse effects. For overcoming these problems, an enteric-coated formulation of mycophenolate sodium has been developed, but pharmacokinetic data of mycophenolic acid release from this formulation are scanty. Design, setting, participants, & measurements: Pharmacokinetic studies in 32 kidney transplant recipients who were given the enteric-coated formulation of mycophenolate sodium (n 12) or mycophenolate mofetil (n 20) were performed. The profiles of mycophenolic acid from the two formulations at months 6, 12, 18, and 24 after transplantation were compared. Subsequently, all patients who were receiving the enteric-coated formulation were shifted to mycophenolate mofetil, and the pharmacokinetic evaluations were repeated. Results: At month 6 after surgery, aberrant and variable pharmacokinetic curves were found in patients who were given the enteric-coated formulation, whereas those who were taking mycophenolate mofetil had regular mycophenolic acid kinetic profiles. Patients who were taking the enteric-coated formulation had mycophenolic acid time of occurrence for maximum drug concentration that ranged from 0 to 480 min and higher dosage-adjusted mycophenolic acid trough levels compared with patients who were given mycophenolate mofetil. Conversion from the enteric-coated formulation of mycophenolate sodium to mycophenolate mofetil resulted in an improvement of the mycophenolic acid kinetics profiles. Conclusions: Given the emerging clinical benefit of mycophenolic acid monitoring in the transplant setting, therapeutic drug monitoring problems with the enteric-coated formulation of mycophenolate sodium should be taken into account. Clin J Am Soc Nephrol 2: 1147–1155, 2007. doi: 10.2215/CJN.02820707

Following 10 years of clinical use of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid, the FDA has approved enteric-coated mycophenolate sodium (EC-MPS). EC-MPS was developed to reduce the upper-gastrointestinal (GI) effects of MMF. Unlike oral MMF, where absorption starts in the stomach, EC-MPS releases MPA in the small intestine. Along with the pharmacology and pharmacokinetics, three randomized, controlled clinical trials in solid-organ transplantation, comparing MMF and EC-MPS, are reviewed. Disappointingly, EC-MPS was similar to MMF in efficacy and safety and did not significantly improve the GI side effects. Moreover, bioequivalence dosing has only been established with concomitant ciclosporin. The pharmacokinetic characteristics must be studied in greater detail. EC-MPS is a safe and effective immunosuppressive agent approved for use in the prevention of acute rejection after renal transplantation. However, the anticipated improvement of GI side effects has not been forthcoming.

Summary Background Approximately 75–95% of patients with cutaneous lupus erythematosus respond to antimalarial therapy and/or topical glucocorticosteroids. Immunosuppressive agents are usually considered a second-line approach in patients with resistant disease. Objectives This was a prospective, nonrandomized, open pilot study to evaluate the efficacy of mycophenolate sodium monotherapy in patients with recalcitrant subacute cutaneous lupus erythematosus (SCLE). Methods Monotherapy with oral enteric-coated mycophenolate sodium 1440 mg daily was given for a total of 3 months. Treatment outcome was evaluated by means of a validated clinical score for cutaneous lupus erythematosus, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), as well as 20-MHz ultrasound measurements and colorimetry. Safety assessment included the monitoring of adverse effects and clinical laboratory parameters. Results Ten patients with active SCLE resistant to at least one standard therapy were included in the trial. Mycophenolate sodium led to a remarkable improvement of skin lesions, resulting in a significant decrease of the mean ± SD CLASI from 10·8 ± 6·0 at the beginning to 2·9 ± 2·6 at the end of therapy. Clinical improvement was confirmed by ultrasonographic assessments and colorimetry. No serious side-effects were noted. Conclusions Mycophenolate sodium is beneficial and safe in the treatment of patients with SCLE that failed standard therapy. However, these preliminary data must be confirmed by randomized controlled trials including a larger sample size.

The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS) may lead to different MPA predose (C0) levels compared with mycophenolate mofetil (MMF). A post hoc analysis was performed on MPA morning predose values assessed in 88 maintenance renal transplant patients from three studies converted from MMF (1000 mg twice a day) to equimolar EC-MPS (720 mg twice a day) or vice versa, both in combination with cyclosporine. The median MPA predose level was approximately 30% higher when patients received EC-MPS (2.40 microg/mL; range, 0.49-39.30 microg/mL) compared with MMF (1.83 microg/mL; range