Comparative efficacy of mycophenolate sodium (MPS) and mycophenolate mofetil (MMF) with and without cyclosporine in rat transplantation models.
BACKGROUND
ERL is the enteric-coated sodium salt of mycophenolic acid, presently in clinical development. The drug substance mycophenolate sodium (MPS) was evaluated in rat transplantation models and compared with mycophenolate mofetil (MMF) for therapeutic window and synergy with cyclosporine (CsA).


METHODS
Allotransplantation was performed in the Dark Agouti-to-Lewis (DA-to-Lewis; kidney, heart, and aorta) and Brown Norway-to-Lewis (BN-to-Lewis; kidney) strain combinations, and hamster heart xenotransplantation was performed in athymic and euthymic Lewis rats. The compounds were administered daily orally, starting the day of transplantation.


RESULTS
In kidney and heart transplantation the minimal efficacious dose of CsA was 5.0 mg/kg/d. For MPS this dose was 10 mg/kg/d in BN-to-Lewis kidney transplantation, 20 mg/kg/d in DA-to-Lewis heart transplantation, and 10 mg/kg/d in hamster-to-athymic rat heart transplantation. At these doses the first signs of adverse effects were evident, indicating a narrow therapeutic window. No window was established for MMF in these models or for MPS in DA-to-Lewis kidney transplantation. There was no potential synergy between CsA and MPS or MMF regarding efficacy, but fewer side effects were noted in efficacious combinations, in particular for MPS. In aorta transplantation, MPS and MMF dose-dependently inhibited intima thickening. The combination of 20 mg/kg/d MPS and 10 mg/kg/d CsA gave long-term survival of hamster-to-rat xenografts.


CONCLUSIONS
Despite the overall comparable efficacy and narrow therapeutic window of MPS and MMF when given alone, MPS apparently is better tolerated than MMF in some of the transplant models. The combination of these agents with CsA allows fine-tuning between optimal immunosuppression and adverse side effects.
Schuurman
H J
HJ
Transplantation Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. henk.schuurman@immergebt.com
Pally
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Fringeli-Tanner
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Papageorgiou
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D000818:Animals; D001011:Aorta / Q000637:transplantation*; D006224:Cricetinae; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008647:Mesocricetus; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid