Suppression of acute rejection in allogeneic rat lung transplantation: A study of the efficacy and pharmacokinetics of rapamycin derivative (SDZ RAD)used alone and in combination with a microemulsion formulation of cyclosporine

Background: The novel immunosuppressant SDZ RAD, 40-0 (2-hydroxyethyl)rapam ycin, is an orally active rapamycin analogue developed for use in combinati on with cyclosporine (Neoral(R)). The present study was designed to evaluat e the efficacy of SDZ RAD, Neoral(R), or a combination of both drugs for su ppression of acute rejection in an allogeneic, unilateral rat lung transpla nt model. Methods: Brown-Norway (RT1(n)) donor lungs were implanted into Lewis (RT1(1 )) recipients that were observed for 21 days. Postoperative evaluation incl uded daily weights, serial chest radiographs, drug trough levels, and histo logy scores of the transplanted lung on the day of sacrifice. Treatment gro ups were comprised of rats treated orally with the RAD vehicle as controls (n = 6); SDZ RAD 2.5 mg/kg/day (n 9); Neoral(R) 7.5 mg/kg/day (n = 8); Neor al(R) 2.5 mg/kg/day (n = 6); SDZ RAD 2.5 mg/kg/day plus Neoral(R) 7.5 mg/kg /day (n = 7); and Neoral(R) 2.5 mg/kg/day plus SDZ RAD 2.5 mg/kg/day (n = 6 ). Results: The results of this study showed that neither monotherapy with 2.5 mg/kg/day of Neoral(R), nor 2.5 mg/kg/day of SDZ RAD prevented severe acut e rejection in unilateral lung transplant recipients. Furthermore, despite high dose (7.5 mg/kg/day) Neoral(R) treatment, graft histology showed moder ate rejection. However, addition of 2.5 mg/kg/day of SDZ RAD to 7.5 mg/kg/d ay of Neoral(R) completely prevented histologic rejection in four of seven grafts, although the remaining 3 grafts showed minimal rejection. This comb ination resulted in significantly higher RAD trough levels when compared to SDZ RAD treatment alone. Combining a lower dose of Neoral(R) (2.5 mg/kg/da y) with 2.5 mg/kg/day of SDZ RAD resulted in less weight loss and improved animal health; however, the histology of lung grafts in these rats showed m ild rejection. Conclusions: This is the first study on the efficacy of the novel rapamycin derivative SDZ RAD for the control of acute lung allograft rejection. Resu lts showed that acute. unilateral rat lung allograft rejection is refractor y to monotherapy with either high dose Neoral(R) or SDZ RAD. The two regime ns of combined treatment with Neoral(R) plus SDZ RAD used in these studies produced either minimal rejection and reduced tolerability or mild rejectio n and better tolerability and showed potentiation of immunosuppression when both drugs were used together. Additional investigation of these two drugs is needed, however, to devise regimens that produce both high immunosuppre ssive efficacy and good tolerability.