Combined immunosuppression with cyclosporine (Neoral) and SDZ RAD in non-human primate lung transplantation: Systematic pharmacokinetic-based trials to improve efficacy and tolerability

Background. We studied the efficacy and tolerability of combined immunosuppressive therapy with cyclosporine A microemulsion (Neoral) plus the macrolide SDZ RAD 40-0 (2-hydroxyethyl) rapamycin (RAD) in a stringent cynomolgus monkey lung graft model in comparison with cyclosporine or SDZ RAD monotherapy. Methods. Thirty-nine cynomolgus monkeys received mixed lymphocyte reaction (MLR) mismatched unilateral lung transplants. Immunosuppressants were administered orally as single daily doses. The observation period was 28 days and follow-up included serial trough blood drug concentrations measured by high performance liquid chromatography/mass spectrometry, blood analyses, chest radiographs, open lung biopsies, as well as tissue drug concentrations and graft histology at necropsy. Results. Graft biopsies in monkeys treated with vehicle (n=4), Neoral (day 1-7:150 mg/kg/day; day 8-28: 100 mg/kg/day; n=6; mean±SE trough level (MTL): 292±17 ng/ml) or SDZ RAD monotherapy (1.5 mg/kg/day; n=6; MTL: 15±1 ng/ml) showed severe rejection. Coadministration in two transplant monkeys of Neoral (1501100 mg/kg/day) and SDZ RAD (1.5 mg/kg/day) caused their early death. In both animals, SDZ RAD blood levels were more than 5-fold higher than under monotherapy (MTL: 82±18 ng/ml). Simultaneous administration (n=6) of Neoral (150/100 mg/kg/day; MTL: 217±16 ng/ml) and SDZ RAD (0.3 mg/kg/day; MTL: 24±2 ng/ml) improved graft outcome (mild rejection). Side effects included renal failure (n=2) and seizures (n=1). Three monkeys survived to day 28. In this group the MTL for cyclosporin was 143±13 and for RAD 38±3. Staggered treatment completely prevented rejection in four of six grafts. However, five of six monkeys had moderate to severe diarrhea. In a concentration-controlled trial of simultaneously administered Neoral and SDZ RAD in transplant monkeys (target SDZ RAD MTL: 20-40 ng/ml; cyclosporine MTL: 100 200 ng/ml) all six monkeys survived with improved drug tolerability and an average biopsy score of mild rejection. Conclusion. Combination of orally administered SDZ RAD and Neoral showed excellent immunosuppressive efficacy in a stringent lung transplant model. The drug interaction and the narrow therapeutic index of this drug combination required careful dose adjustments to optimize tolerability and efficacy.