Efficacy of mycophenolate sodium as monotherapy and in combination with Fty720 in a Da-to-lewis-rat heart-transplantation model

Background. Mycophenolate sodium (MPS), which is in clinical development as an enteric-coated tablet (Myfortic), has not yet been characterized as a combination partner of FTY720. We therefore report here the effects of MPS and FTY720 mono and combination therapy in a rat heart allograft model. Methods. Heterotopic heart allotransplantation was performed in the DA-to-Lewis-strain combinations. Groups of six rats were treated with placebo, MPS monotherapy, FTY720 monotherapy, and their combination. To circumvent pharmacokinetic problems, MPS was administered by Alza minipumps, while FTY720 was administered by gavage, both for 4 weeks. Graft survival was monitored daily, followed up by histology. Body weight and hematological parameters were determined at 1 and 4 weeks. Results. The median survival time (MST) was 6 days for placebo, 6, 14.5, and more than 56 days for doses 3, 10, and 30 mg/kg per day MPS, with severe side effects (diarrhea, weight loss, lymphopenia) at the highest dose, and 7 and 8 days for the 0.03 and 0.1 mg/kg per day FTY720. The combination of 3 mg/kg per day MPS with these two FTY720 doses still resulted in rejection under treatment. However, 10 mg/kg per day MPS in combination with 0.03 or 0.1 mg/kg per day FTY720 yielded MSTs of 41 and 43.5 days, respectively, well beyond the 4-week treatment period. Both combination regimens were well tolerated. Both FTY720 doses combined with the highest MPS dose again caused severe side effects. Conclusions. MPS in monotherapy and combined with FTY720 resulted in steep dose-response curves. However, well tolerated combination regimens could be defined that prevented rejection.