COADMINISTRATION OF MICROEMULSION CYCLOSPORINE AND THE NOVEL LEFLUNOMIDE MALONONITRILAMIDE ANALOG, HR1279, MORE EFFECTIVELY SUPPRESSES RAT LUNG ALLOGRAFT REJECTION THAN MICROEMULSION CYCLOSPORINE PLUS LEFLUNOMIDE

Abstract

522 HMR 1279 (279) is one of two new malononitrilamides being developed as alternatives to leflunomide (LFM) as immunosuppressants for transplantation. This study evaluated the relative immunosuppressive efficacies of daily PO(gavage) treatment with cyclosporine (Neoral), LFM or 279 monotherapy and combined therapy with Neoral plus either LFM or 279 in an aggressively rejecting rat lung allograft model. Method: 36 Lew recipients of unilateral BN lungs were monitored by daily weights, chest radiographs, drug trough levels (HPLC for 279 and A77 1726, the active metabolite of LFM) and LC/MS for CsA until d 21 when grafts were removed for blinded histologic grading by ISHLT criteria. Groups (n = 6 for all groups) were: untreated controls, Neoral (7.5 mg/kg), 279 (10 mg/kg) or LFM (10 mg/kg); the same doses were then used in combination therapy regimens: Neoral + LFM and Neoral + 279.Results: Other than 1 death, all recipients remained clinically healthy with an average 4-6% percent change in body wt. Chest radiographs showed moderate to complete opacification of grafts in control rats on d 7 and by d 14 in LFM and 279 monotherapy groups, but were clear on d 21 in the remaining groups. Histologic scoring (fig) showed moderate to severe rejection in grafts from control rats and rats treated with 279 or LFM. The efficacy of Neoral alone was not improved by its combination with LFM even though combination therapy significantly (p<0.001) increased trough serum levels of A77 1726 (1.9±0.7 ug/ml)compared to levels during LFM monotherapy (0.2±0.2 ug/ml). Neoral + 279, however, suppressed histologic rejection substantially more than any other treatment regimen. CsA levels were not affected by coadministration of Neoral with LFM or 279. Conclusions: 1) Neoral, LFM and 279 monotherapy suppress lung graft rejection much less effectively than BN to Lew heart graft rejection based on previous work using identical drug regimens, 2) Lung graft rejection is most effectively suppressed by Neoral + 279, 3) In contrast, the efficacy of Neoral is not improved by coadministration of LFM, 4) This the first study to show 279 is more immunosuppressive than LFM; the reasons for the differences in efficacies between the analog and parent drug are being investigated.