COADMINISTERED NEORAL AND THE NEW RAPAMYCIN DERIVATIVE, SDZ RAD, FOR NONHUMAN PRIMATE LUNG TRANSPLANTATION: SYSTEMATIC PHARMCOKINETIC-BASED TRIALS TO MAXIMIZE EFFICACY AND TOLERABILITY

Abstract

677 This is the first preclinical study to exploit blood drug levels (PK) to guide trial design and drug tissue levels to interpret adverse events. A stringent lung graft model combined with complex interactions between Neoral and RAD required a thorough understanding of the relationships among PK,efficacy and toxicity at each stage of the study to insure progressive improvements. Method: 39 cynomolgus monkeys were recipients of MLR-mismatched unilateral lung transplants (tx) and sacrificed either at the end of 28 daily PO drug treatments or earlier if clinically ill. Follow-up included serial trough blood drug levels (LC/MS), blood chemistries, chest radiographs and tissue drug levels and graft biopsies at necropsy. At each stage of the study, existing data from tx and nontx monkeys were used to design treatment regimens for subsequent groups. Results: Perioperative complications excluded 3 monkeys from analysis. Biopsies of grafts in vehicle treated monkeys (n=4) and those treated with Neoral (150 mg/kg, d 1-7; 100 mg/kg, d 8-28; n = 6; mean±SE trough level(MTL):276±17 ng/ml) or RAD (1.5 mg/kg; n = 6; MTL:13±1 ng/ml) monotherapy showed severe rejection. Combining Neoral (150/100mg/kg) and RAD(1.5 mg/kg) in 2 tx monkeys caused early death in both animals and produced a more than 4-fold increase in RAD trough levels (>80 ng/ml). A PK study in nontx monkeys on the same drug regimen confirmed equally elevated RAD trough levels (MTL:101±20 ng/ml). In nontx monkeys co-administration of Neoral and RAD required a 4-fold decrease in the RAD dose to achieve RAD levels of less than 25 ng/ml. In tx monkeys, Neoral (150/100 mg/kg; MTL:205±12 ng/ml) + RAD (0.3 mg/kg; MTL:21±2 ng/ml) improved graft outcome (mild rejection), but 3 monkeys were euthanized on days 21-23 due to renal failure(n=2) and seizures (n=1). In an attempt to improve efficacy and safety and reduce potential drug interaction staggered administration was compared to simultaneous treatment in nontx monkeys using a Neoral dose of 50 mg/kg (to limit CsA toxicity) and a RAD dose of 1.5 mg/kg (to maintain efficacy). Staggered treatment resulted in significantly lower RAD trough levels(MTL:40±6ng/ml) than simultaneous treatment(MTL:54±4ng/ml;p<0.04) while CsA-levels were comparable (MTL: sim. 171±14 ng/ml, stag: 179±23 ng/ml). The staggered regimen in tx monkeys resulted in no rejection in 4 grafts and minimal or mild rejection in 1 graft each. However, 5/6 monkeys had moderate or severe diarrhea (3 requiring euthanasia before d 28). These results led us to perform a concentration-controlled trial (CCT) of simultaneously administered Neoral and RAD in tx monkeys (target RAD MTL:20-40 ng/ml; CsA MTL:100-200 ng/ml). All 6 tx monkeys survived until study completion with improved drug tolerability and an average biopsy score of only mild rejection. Compared to RAD monotherapy, colon RAD tissue levels in the staggered and CCT group were 12x and 3x greater, respectively. Conclusion: 1) A combination of orally administered RAD and Neoral showed unprecedented efficacy of an immunosuppressive regimen in a stringent transplant model. 2) Complex Neoral-RAD drug interactions in monkeys necessitated the use of PK and drug tissue levels to guide trial design and interpret adverse events leading to improvements in efficacy and safety 3) The best balance of efficacy and tolerability was achieved in lung transplanted monkeys with a concentration-controlled, rather than fixed dose regimen. Funded by Novartis.