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)rapamycin, is an orally active rapamycin analogue developed for use in combination with cyclosporine (Neoral). The present study was designed to evaluate the efficacy of SDZ RAD, Neoral, or a combination of both drugs for suppression of acute rejection in an allogeneic, unilateral rat lung transplant model.


METHODS
Brown-Norway (RT1n) donor lungs were implanted into Lewis (RT1l) recipients that were observed for 21 days. Postoperative evaluation included daily weights, serial chest radiographs, drug trough levels, and histology scores of the transplanted lung on the day of sacrifice. Treatment groups were comprised of rats treated orally with the RAD vehicle as controls (n = 6); SDZ RAD 2.5 mg/kg/day (n = 9); Neoral 7.5 mg/kg/day (n = 8); Neoral 2.5 mg/kg/day (n = 6); SDZ RAD 2.5 mg/kg/day plus Neoral 7.5 mg/kg/day (n = 7); and Neoral 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, nor 2.5 mg/kg/day of SDZ RAD prevented severe acute rejection in unilateral lung transplant recipients. Furthermore, despite high dose (7.5 mg/kg/day) Neoral treatment, graft histology showed moderate rejection. However, addition of 2.5 mg/kg/day of SDZ RAD to 7.5 mg/kg/day of Neoral completely prevented histologic rejection in four of seven grafts, although the remaining 3 grafts showed minimal rejection. This combination resulted in significantly higher RAD trough levels when compared to SDZ RAD treatment alone. Combining a lower dose of Neoral (2.5 mg/ kg/day) 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 mild 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. Results showed that acute unilateral rat lung allograft rejection is refractory to monotherapy with either high dose Neoral or SDZ RAD. The two regimens of combined treatment with Neoral plus SDZ RAD used in these studies produced either minimal rejection and reduced tolerability or mild rejection 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 immunosuppressive efficacy and good tolerability.
Hausen
B
B
Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University Palo Alto, California, USA.
Boeke
K
K
Berry
G J
GJ
Segarra
I T
IT
Christians
U
U
Morris
R E
RE
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004359:Drug Therapy, Combination; D004655:Emulsions; D000068338:Everolimus; D006084:Graft Rejection / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D011859:Radiography; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus