Enteric-coated mycophenolate sodium in renal transplantation

teaser

Bruno Vogt
MD

Michel Burnier
MD
Nephrology and Hypertension Unit
Centre Hospitalier Universitaire Vaudois
Lausanne
Switzerland
E: [email protected]

Inhibitors of inosine monophosphate dehydrogenase (IMPDH) are effective immunosuppressive agents. Mycophenolate mofetil (MMF, CellCept(R); Roche), a prodrug of mycophenolic acid (MPA), is a commonly used IMPDH inhibitor in solid organ transplantation. However, its use is associated with a high incidence of gastrointestinal (GI) adverse events. Enteric-coated mycophenolate sodium (EC-MPS, Myfortic(R); Novartis Pharma) is a new MPA formulation developed to improve MPA-related upper GI symptom burden by delaying the release of MPA until reaching the small bowel. EC-MPS has recently been approved in Europe and the USA for the prophylaxis of organ rejection in renal transplantation. EC-MPS is available in the form of 180 mg and 360 mg tablets to be administered orally on a twice-daily treatment schedule (ie, 720 mg twice daily in adults) in combination with ciclosporin and corticosteroids.

Pharmacokinetics
EC-MPS (Myfortic) is an enteric-coated formulation of the monosodium salt of mycophenolic acid (MPA). It lacks the mofetil ester of MMF, resulting in a lower molecular weight. MPA manifests high aqueous solubility and intestinal permeability, consistent with Biopharmaceutics Classification System Class I features. MPA is not released from EC-MPS before the alkaline environment of the small intestine has been reached. Dissolution studies with EC-MPS have shown that MPA is maximally released at pH 6.0-6.8.1 A pharmacokinetic study in renal transplant patients showed that EC-MPS 720 mg provides an MPA exposure bioequivalent to 1,000 mg of MMF.(1) A subsequent meta-analysis of pharmacokinetic data from three clinical trials confirmed the bioequivalence of equimolar doses of EC-MPS and MMF for both: (a) MPA area under the time-concentration curve (AUC) and (b) MPA maximum plasma concentration (C(max)).(2) Consistent with the enteric-coating of the formulation, median Cmax occurs after approximately two hours, which is 1.25 hours later compared with MMF. EC-MPS follows dose-proportional pharmacokinetics and the mean absolute bioavailability of MPA from EC-MPS amounts to 71%.(3) Coadministration of EC-MPS with food has no effect on systemic MPA exposure; hence, the drug may be taken with or without food. MPA is primarily metabolised in the liver to an inactive metabolite, myco‑phenolic acid glucuronide (MPAG), the major urinary excretion product. MPAG is also excreted into the bile; thereafter MPAG is hydrolysed in the intestine and reabsorbed as MPA (ie, enterohepatic circulation). The mean elimination half-life of MPA is 8�16 hours; respective values for MPAG are 13-17 hours.(4)

Efficacy and safety
Two randomised, double-blind phase III studies compared the efficacy and safety of EC-MPS with MMF in de-novo (n = 423) and maintenance (n = 322) renal transplant recipients. These studies have shown that EC-MPS 720 mg twice daily is therapeutically equivalent to MMF 1,000 mg twice daily,(5) with comparable outcomes also upon long-term administration of up to three years.(6) In addition, renal transplant patients on MMF can be safely converted to EC-MPS.(7,8)  There was no difference between EC-MPS and MMF in the incidence of efficacy failure (ie, biopsy-proven rejection, graft loss or death) and adverse event profile. Moreover, results from subpopulation analyses suggest that EC-MPS can be used efficiently and safely in diabetic renal transplant patients,(9) elderly patients ≥ 65 years,(10) African-American recipients(11) and in patients receiving different induction therapies.(12)

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The Myfortic Prospective Multicenter Study (myPROMS) was an international prospective open-label clinical trial designed to assess the efficacy and safety of EC-MPS in a large population of approximately 1,400 de-novo and maintenance renal transplant recipients. The study had a predefined core protocol, with 14 substudies that addressed a number of different aspects of EC-MPS treatment. All study participants received EC-MPS and ciclosporin, with or without corticosteroids. In the de novo renal transplant population (n = 456), pooled analysis of three myPROMS substudies at 12 months (performed in France, Germany and the USA) yielded a treatment failure rate of 25.9%, with biopsy-proven rejection alone accounting for 22.1% of failures.(13) One-year patient and graft survival were 98.7% and 96.9%, respectively. Overall, 28% of patients required a dose reduction, with leucopenia (8.1%) being the most frequent reason.(14) GI-related adverse events were reported in 77.6% of patients, being mostly mild or moderate in severity (> 90%). EC-MPS discontinuation due to GI events was required in 2.2% of patients.(13) Another pooled analysis of myPROMS, considering de novo renal transplant recipients from Switzerland, the Czech Republic, Poland and Greece (n = 140), yielded �almost identical 12-month results.(15)

In the population of maintenance renal transplant patients (recruited in Asia, Europe and Latin America), the pooled six-month analysis of three myPROMS substudies (n = 588) showed the following results. After conversion from MMF to EC-MPS, the cumulative incidence of adverse events was 74.3%. GI-related adverse events were reported by 23.5% of patients, being mostly mild in severity. Overall, 6.3% of patients required a dose reduction. The rate of dose adjustment as a result of GI-related adverse events was 2.2%.(16) The results from myPROMS support the good efficacy and tolerability profile of EC-MPS in renal transplant patients already observed in preceding trials.

Health-related quality of life
The PROGIS study (Patient-Reported Outcomes in renal transplant recipients with or without Gastro-Intestinal Symptoms) assessed the impact of GI complaints and symptom severity on health-related quality of life in the context of a multicentre open-label prospective trial.(17) The study evaluated the benefit of converting renal transplant recipients with GI complaints from MMF to EC-MPS using validated self-administered patient questionnaires. In total, 177 patients were converted from MMF to equimolar EC-MPS because of GI adverse events. The study showed that converting patients with mild, moderate or severe GI complaints from MMF to EC-MPS significantly reduced GI-related symptom burden and improved patient functioning and wellbeing. A more recent open-label, prospective three-month study in a large population of renal transplant recipients (n > 700) confirmed that converting maintenance patients with GI complaints during MMF therapy to EC-MPS reduced the incidence of GI complications and significantly improved GI symptom severity.(18)

Conclusion
EC-MPS is a new MPA formulation developed to improve MPA-related upper GI side-effects by delaying the release of MPA until reaching the small bowel. Several studies in renal transplant recipients demonstrated its efficacy and improved safety profile. The drug is therapeutically equivalent to MMF when administered at equimolar doses. Moreover, patients can be safely converted from MMF to EC-MPS, if needed. Preliminary data suggest a reduced GI-related symptom burden and improved patient wellbeing with EC-MPS treatment. However, this needs to be substantiated in future trials.

References

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