Combined immunosuppression with cyclosporine (neoral) and SDZ RAD in non-human primate lung transplantation: systematic pharmacokinetic-based trials to improve efficacy and tolerability.
Transplantation
; 69(1): 76-86, 2000 Jan 15.
Article
in En
| MEDLINE
| ID: mdl-10653384
ABSTRACT
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.
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Database:
MEDLINE
Main subject:
Lung Transplantation
/
Cyclosporine
/
Sirolimus
/
Immunosuppressive Agents
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Year:
2000
Type:
Article