A novel leflunomide derivative, FK778, for immunosuppression after kidney transplantation in dogs

Background. Leflunomide and its metabolite, A 77 1726, interfere with pyrimidine metabolism and exert potent immunosuppression in experimental organ transplantation. However, clinical use of the agents has been restrained because of an extended half-life. FK778, one synthetic malononitrilamide derived from A 77 1726, is synthesized to overcome this problem while maintaining similar therapeutic efficacy. Methods. Immunosuppressive effect ,feet, pharmacokinetics, and adverse events of FK778, as a single drug treatment or combination with tacrolimus or cyclosporine, were determined in a canine kidney transplantation model. The agents were daily administered orally to the animals fir 90 days after surgery. Animal survival, pharmacokinetics, biochemistry, hematology, and histopathology were evaluated. Results. FK778 at 4 mg/kg Prolonged median survival of the control animals from 10 days to 30.5 days. Administration of 4 mg/kg FK778 with 0.3 mg/kg tacrolimus or 10 mg/kg cyclosporine increased median survival to 75.5 days and 50.5 days, respectively. In, combined treatments, trough levels of FK778 at 4 mg/kg ranged between 40 mug/mL, and 100 mug/mL after I month. Vomiting and diarrhea were common in animals given FK778. Bone marrow suppression was seen at higher doses. Conclusions. FK778 is a promising new immunosuppressant that may be used in combination with current. standard drugs in organ transplantation. (Surgery 2002;132:72-9.).