Is EC‐MPS effective in reducing GI toxicity of MPA? At what price?

Mycophenolate mofetil (MMF) and a low-dose calcineurin inhibitor (CNI), with or without steroid treatment, have become a standard long-term maintenance immunosuppressive therapy in pediatric solid organ transplantation (1). Mycophenolic acid (MPA), the active metabolite of MMF, acts by inhibiting inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the biosynthesis of the purine nucleotide guanosine-triphosphate, and thereby efficiently suppressing cellular immunity after solid organ transplantation (2–4). Gastrointestinal complications (GICs) such as diarrhea, nausea or abdominal discomfort are a major problem for approximately one quarter of children receiving MMF. It was suggested that GICs were caused either by MMF itself or its metabolites. Gastric complications of MMF and MPA were thought to be caused directly in the stomach where MPA is rapidly released from its prodrug MMF (7). MPA may produce additional intestinal complications either directly or by the action of its metabolites (7). To avoid repeated episodes of GIC, doctors or patients may reduce, interrupt or even discontinue the MMF therapy. This leads to an increased risk of graft rejection (5). Therefore, enteric coated mycophenolate sodium (EC-MPS) has been introduced to replace MMF and to decrease GIC by prolonged enteric release (7). It was speculated that EC-MPS mainly avoided the local effects of MMF on the gastric and intestinal mucosa. It was shown in a selected adult population with severe GIC is that a switch from MMF to EC-MPS led to fewer GIC and improved quality of life without increasing the rate of rejection (6). This effect was explained by the reduction of peak blood levels of MPA. In adult renal graft recipients it was shown that EC-MPS had the same immunosuppressive efficacy and safety as MMF (7). However, in an unselected group of adult patients randomized studies did not show an overall benefit of EC-MPS on GIC if compared to MMF (7, 8). Data on EC-MPS in transplanted children are scarce. In our own pediatric study on 10 children, we could show that the switch fromMMF to ECMPS was safe and well tolerated. The number of severe GICs, using the gastointestinal symptoms rating scale, decreased significantly (8). Patient non-adherence to drug therapy is a major cause of graft loss (9). It has been shown that the discontinuation of MMF or even a reduction of MMF dose may lead to impaired graft survival (10). It can be speculated that the improvement in health-related quality of life due to fewer GIC may lead to an increase in patient adherence to drug treatment and thereby prolong graft survival, as has been shown in other studies (11). In their article on this issue, Ferraris et al. (12) report, in a small retrospective and weakly stratified study on eight children with GIC during MMF and tacrolimus immunosuppression, significantly reduced MMF-induced GIC after switching to equimolar doses of EC-MPS. It may be speculated that the reduction of GIC by EC-MPS may be due to reduced MPA exposure in the patients; however, Ferraris and other studies did not measure the real drug exposure by therapeutic drug monitoring using the area under the curve concentrations (AUC). Yet, the study of Ferraris et al. (12) is the first to prove that MPA trough levels were not lower after switch from MMF to EC-MPS but even higher, thus showing that the protective effect of EC-MPS was not merely due to a reduction of MPA. Furthermore, the authors show that the cytokine profile was similar before and after the conversion to EC-MPS, suggesting similar immunosuppressive activity in both medications. However, it remains unclear whether the cytokine profile Pediatr Transplantation 2009: 13: 659–66