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 (150/100 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.