Cyclosporin immunosuppression of sheep: pharmacokinetics and allograft survival

A chronically immunosuppressed sheep model was established using a regimen of cyclosporin A (CsA; 2-3 mg/kg twice daily) and ketoconazole (10 mg/kg tw ice daily). Blood CsA concentrations reached a steady-state after 17 days o f treatment. The clearance of CsA decreased from a mean (95% CI) of 9.47 (6 .2-12.7) ml/min/kg after a single (first) dose (3 mg/kg i.v.) to 1.62 (1.38 -1.86) ml/min/kg after 18 days of CsA (3 mg/kg i.v. twice daily) co-adminis tration with ketoconazole. These data indicated that the combination of CsA and ketoconazole could be used to give stable high concentrations of CsA i n the sheep. Using this regimen in the sheep. the long-term survival of ski n allografts was monitored as an indicator of effective immunosuppression. CsA in blood was measured daily and CsA dose adjusted to various target con centration ranges. Provided that the trough concentration of blood CsA was maintained between 1500-2500 mg/l, long-term healthy skin allografts were m aintained on the sheep without significant adverse effects on haematologica l or biochemical parameters. (C) 2001 Elsevier Science B.V. All rights rese rved.