The relationship of blood concentrations of rapamycin and cyclosporine to suppression of allograft rejection in a rabbit heterotopic heart transplant model

Heterotopic heart transplants were performed on 50 New Zealand white rabbits. Groups of 5 rabbits were randomly assigned to receive, through an intravenous route, rapamycin (RAPA) or cyclosporine at the following doses: RAPA (0.05, 0.1, 0.5, and 1.0 mg/kg/day); CsA (5.0, 10.0, and 15.0 mg/kg/day). Drug vehicle and saline controls were also included. Trough blood concentrations were monitored in both RAPAand CsA-treated groups on a weekly basis throughout the study. Biochemical assessment of renal and liver function was performed at the beginning and end of the study. Animals receiving RAPA exhibited excellent allograft survival; only two animals in the lowest dosage group (0.05 mg/kg/day) rejected their grafts. In contrast, no rejection occurred in the CsA-treated groups. Animals that rejected their grafts were maintained on the drug until the endpoint of the study was reached at 60 days post-transplant to monitor drug induced side-effects. In some instances animals were sacrificed prior to this time due to infectious and other complications. No significant changes in renal or liver function were noted in the RAPA-treated group, while in the group of animals receiving the highest dose of CsA (15.0 mg/kg/day) a significant decrease in creatinine clearance was noted. A correlation was shown to exist between dose and the trough concentrations of both drugs. The whole-blood concentrations of RAPA that resulted in maximal efficacy with minimal toxicity was in the range of 10-60 Mg/L. Rabbits having trough whole-blood concentrations of <10 ngfL rejected their grafts. A much wider therapeutic range for CsA (50-300 ngfL) was noted. The results suggest that RAPA is as efficacious as CsA in prevention of allograft rejection in the animal model tested. The therapeutic monitoring of trough blood concentrations of RAPA, as with CsA, may be useful in guiding dosage adjustments to maximize the immunosuppressive efficacy while minimizing drug-induced side-effects.