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Laparoscopic sleeve gastrectomy induces weight loss via the creation of a restrictive gastric tube for early satiety and is associated with an accelerated gastric transit time. A prospective, single-dose pharmacokinetic study was performed, prior to and after laparoscopic sleeve gastrectomy, for tacrolimus, extended-release tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium. The study included 12 morbidly obese patients in chronic renal failure. The median decrease in body mass index was 8.8 kg/m2 with an excess body weight loss of 54.9%. The AUC24 of all drugs were increased after laparoscopic sleeve gastrectomy by 46%, 55%, 77%, and 74%, respectively. The maximum concentrations were increased for tacrolimus, extended-release tacrolimus, and mycophenolate mofetil by 43%, 46%, and 65%. The apparent total clearances were decreased for tacrolimus, mycophenolate mofetil, and enteric-coated mycophenolate sodium by 36%, 57%, and 38%. Laparoscopic sleeve gastrectomy can be associated with significant changes in pharmacokinetics of the drugs evaluated. The mechanism is likely decreased apparent drug clearance due to an increased drug exposure (from a more distal site of intestinal absorption with decreased intestinal metabolism), or decreased clearance (liver metabolism). Adapting the monitoring of immunosuppression will be important to avoid overdosing and potential side effects.

Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation.A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively.The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P .05). However, no differences were found according to genotype distribution in all groups (P.05).Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects.

Vaccination can prevent infection and disease due to SARS-CoV-2. Early reports indicate that immune suppressed or immune compromised populations have reduced immune responses to US emergency use authorized (EUA) vaccines. Patients with autoimmune disorders are at risk for severe COVID-19, and are frequently immune suppressed related to therapy, the underlying disease, or both. Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies that interrupt neuromuscular transmission. Chronic immune suppressive therapy is typically required. We report the case of a 74 year old woman with MG receiving mycophenolate, prednisone, and eculizumab in whom mRNA vaccination failed to elicit detectable circulating vaccine-specific IgG or IFN-γ T cell responses. Eculizumab was discontinued, and repeat vaccination with two doses of an alternative EUA mRNA vaccine led to circulating IgG specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein, and to detectable S-specific T cell responses. While it is not known if these responses will protect against SARS-CoV-2 infection or disease, a repeat course of mRNA vaccination appears to be safe and was broadly immunogenic in this individual., Highlights • T and B cell immune responses to SARS-CoV-2 mRNA vaccine reduced in an immune suppressed patient. • Repeat vaccination course with an alternative mRNA vaccine led to detectable, specific T and B cell responses. • Persons with autoimmune disease receiving immune suppression may benefit from additional doses of vaccine.

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.

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.

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 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.

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) 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.

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.

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.

Mycophenolic acid (MPA), a reversible inhibitor of inosine 5''-monophosphate dehydrogenase (IMPDH), selectively inhibits T- and B-cell proliferation. MPA exposure correlates inversely with the risk of acute rejection. Mycophenolate mofetil (CellCept; MMF) is an immediate-release formulation of MPA that is absorbed in the stomach and small intestine. Enteric-coated mycophenolate sodium (myfortic; EC-MPS) delays MPA release until the small intestine. There are some indications that EC-MPS may be associated with improved gastrointestinal (GI) toxicity. It is widely believed that systemic MPA exposure determines the extent of GI toxicity. However, intestinal cells absorb purines locally from the gut lumen via passive diffusion and a specific transport mechanism. It seems likely that local, rather than systemic, MPA exposure is responsible for GI events. Acyl-MPAG, a toxic metabolite of MPA, may be produced by GI cells contributing to MPA-related gut toxicity, suggesting that measures to alter the rate or location of MPA absorption could be beneficial. Lastly, the release of N-(2-hydroxyethyl)morpholine following deestification of MMF may have local irritative effects on gastric mucosal cells. Research which more closely focuses on the local gut pathobiology of MPA-containing drugs may provide a much clearer understanding of the dose-limiting toxicity of this drug class.

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.

The introduction of mycophenolate mofetil (MMF)--the morpholino ester prodrug of mycophenolic acid (MPA)--has improved graft and patient survival, but its use has been linked with the occurrence of adverse events, particularly gastrointestinal (GI) side effects. These can be sufficiently severe to require dose reductions or discontinuation, which may lead to acute rejection episodes or graft failure. An enteric-coated formulation delivering mycophenolic acid-enteric-coated mycophenolate sodium (EC-MPS)-has been developed with the aim of improving upper GI tolerability. Therapeutic equivalence of EC-MPS 720 mg b.i.d. vs MMF 1000 mg b.i.d. has been established in a pivotal phase III, 12-month, international, randomized, double-blind, parallel group study, involving patients undergoing de novo renal transplantation. The incidence of efficacy failure (composite variable of biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up) was similar between the two groups at 6 months (EC-MPS 25.8% vs MMF 26.2%; 95% CI [-8.7, +8.0]), demonstrating therapeutic equivalence. Efficacy failure remained similar between the two treatment groups at 12 months. The overall incidence of adverse events and GI side effects were also comparable between treatment groups throughout the 12-month study period, although fewer patients in the EC-MPS group experienced study drug discontinuations, interruptions, or dose reductions (12 months: EC-MPS 15.0% vs MMF 19.5%). Subgroup analysis revealed similar safety profiles for EC-MPS and MMF in elderly patients and patients with diabetes at baseline. The EC-MPS 720 mg b.i.d. and MMF 1000 mg b.i.d. show therapeutic equivalence in de novo renal transplant patients. Therefore, EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft function and survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is an advanced formulation delivering mycophenolic acid (MPA), developed with the objective of improving MPA-related upper GI adverse events. A pivotal, 12-month, phase III, randomized, multicenter, double-blind, double-dummy, parallel group study investigated whether stable renal transplant patients can be converted from MMF to EC-MPS therapy without compromising tolerability or efficacy. Stable renal transplant recipients received either MMF, 1000 mg b.i.d. (n=159), or EC-MPS, 720 mg b.i.d. (n=163), for 12 months. The incidence of GI adverse events was comparable between both treatment groups at 3 and 6 months, but there was a trend toward reduced severity of GI side effects in the EC-MPS group. There were fewer serious adverse events with EC-MPS and significantly fewer serious infections (P

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.

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.

Mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids, improves long-term graft survival in renal transplant recipients. However, optimal MMF therapy may be limited by gastrointestinal (GI) intolerance, which may result in the need for MMF dose reduction, interruption, or discontinuation, leading to increased risk of acute rejection. Enteric-coated mycophenolate sodium (EC-MPS) is a new formulation delivering mycophenolic acid developed with the aim of improving upper GI tolerability. A large prospective, open-label, multicenter program (myPROMS: myfortic PROspective Multicenter Study) is underway to determine the efficacy and safety of EC-MPS, in combination with cyclosporine microemulsion (CsA; Neoral) in a large population of de novo and maintenance renal transplant recipients. myPROMS consists of one global protocol with 14 subprotocols. Each subprotocol is designed to address further specific objectives, such as specific patient populations, steroid regimens, and various CsA C2 targets. The preliminary data summarized here are from two subprotocols, which investigated the benefits of converting maintenance renal transplant patients receiving MMF to EC-MPS. The 3-month interim analyses suggest that the conversion from MMF to EC-MPS is well tolerated in maintenance renal transplant recipients.

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.

We strongly reject the charge of misleading reporting raised by Meier-Kriesche and colleagues. The overall reporting quality and transparency is well above average compared to most publications of clinical studies (1). Any potential bias was removed during the extensive review process. The rationale for the development of EC-MPS, ’with the aim to improve upper gastrointestinal (GI) tolerability’ is an important background information and needs to be stated according the CONSORT guidelines (2). The study protocols, objectives, statistics and results (including GI adverse events (AEs)) are presented and discussed in detail (3,4). However, we acknowledge, that some misunderstanding may have been derived from the study size determination description in the manuscript (3) supporting the need of guidelines for the reporting of clinical trials (5). In order to ensure full transparency, details for both studies including comments on the statistic methodology are accessible on www.novartis.com/clinicaltrials.com/ clinicaltrialrepository/login.jsp.

between the mean number of grade 3 rejection episodes between the groups (group 1 0.52 0.1 and group 2 1.68 2.5) p 0.018. There was also a trend towards giving lower doses of CsA in Group 1 (244 mg) compared with Group 2 (293 mg) p 0.06. The number of patients who were switched from cyclosporine to an alternative immunosuppressant agent on clinical grounds (neurotoxicity or two or more episodes of early rejection) were also significantly higher in group 2. Conclusions: At our centre the introduction of cyclosporine profiling and the regular use of C0 and C2 monitoring have improved our results in terms of reducing the number of significant biopsy proven rejection episodes and reducing the number of cyclosporine related side effects.