Potentiation of immunosuppressive efficacy by combining the novel leflunomide analog, HMR 279, with microemulsion cyclosporine in a rat lung transplant model

Background. The novel leflunomide (LFM) analog, HMR 279, potentiates the im munosuppressive efficacy of microemulsion cyclosporine (Neoral(R)) in roden t heart transplantation. The present study was designed to evaluate the imm unosuppressive efficacy of this combination in comparison to the combinatio n of Neoral(R) and LFM in a stringent allogeneic rodent lung transplant mod el. Methods. Donor lungs from Brown Norway rats were implanted into Lewis recip ients and were followed for 21 days. Postoperative monitoring included dail y weight assessment, chest radiographs, drug trough levels measured by high -performance liquid chromatography (LFM/HMR 279) and high-performance liqui d chromatography/mass spectrometry (Neoral(R)), and blinded histology asses sment of the transplanted lung on the day of death based on the Internation al Society for Heart and Lung Transplantation working formulation. Untreate d lung recipients served as controls (group I, n=5), Bats were assigned to the following treatment groups: II, 7.5 mg/kg/day Neoral(R) (n=6); III, to mg/kg/day LFM (n=6); IV, 10 mg/kg/day HMR 279 (n=6); V, 10 mg/kg/day LFM pl us 7.5 mg/kg/day Neoral(R) given simultaneously (n=13); and VI, 10 mg/kg/da y HMR 279 plus 7.5 mg/kg/day Neoral(R) given simultaneously (n=6), Drugs we re given daily by oral gavage, Results. All rats except for one in the HMR 279 monotherapy group survived the follow-up period, The chest radiographs in the control, LFM, and HMR 27 9 monotherapy groups showed moderate to complete opacification of the left chest by postoperative day 7 (controls) and day 14 (LFM, 279), At postopera tive day 21, the Neoral(R) monotherapy and the combination groups showed no signs of opacification in the radiographs. Combination therapies of Neoral (R) plus HMR 279 or Neoral(R) plus LFM:were most successful in preventing h istologic allograft rejection. Combining Neoral(R) and HMR 279 resulted in a significant decrease in the cyclosporine trough levels, Co-administration of LFM plus Neoral(R) resulted in significantly higher LFM trough levels w hen compared to LFM monotherapy. Of all treatments studied, the combination of HMR 279 plus Neoral(R) was tolerated best as assessed by percentage of weight change. Conclusions. This study showed for the first time in a stringent rodent lun g transplant model that combined treatment of LFM or HMR 279 plus Neoral(R) potentiates the immunosuppressive efficacies of these drugs and successful ly prevents allograft rejection.