Efficacy of a new pulmonary cyclosporine a powder formulation for prevention of transplant rejection in rats

Background: The aim of this pilot study was to determine the pharmacokinetics of cyclosporine A powder for inhalation (iCsA) and its rejection prevention efficacy in an experimental lung transplantation model in rats.

Methods: Single-dose pharmacokinetics (10 mg/kg) of pulmonary and orally administered cyclosporine A was determined in whole blood and in lung and kidney tissue. The efficacy of iCsA (2.5 and 5 mg/kg) in inhibiting rejection was determined in an orthotopic left-lung transplantation rat model and compared with orally administered CsA (5 and 10 mg/kg). The ventilation score of lung allografts was assessed with roentgenograms. At Day 10 post-operatively, the rats were terminated and lungs were prepared for histologic analysis.

Results: In the pharmacokinetics study, AUC(0-48) values in blood for iCsA and oral CsA were similar (47,790 +/- 1,739 and 46,987 +/- 2,439 ng h ml(-1), respectively). In contrast, iCsA levels in lung tissue were much higher than oral CsA levels (AUC: 9,152,977 +/- 698,920 vs 84,149 +/- 8,134 ng h g(-1), respectively), showing the effectiveness of the pulmonary administration. In the rejection study, non-treated animals showed complete rejection after 8 days according to roentgenography. Treatment with 5 mg/kg iCsA reduced rejection on Day 10, whereas the 2.5-mg/kg dose did not inhibit rejection. Oral CsA at 10 mg/kg reduced rejection, whereas the 5-mg/kg dose showed hardly any effect on rejection.

Conclusions: We found that iCsA is an effective immunosuppressive formulation, and may become a valuable asset for clinical use in combination with systemic immunosuppression. J Heart Lung Transplant 2009;28:486-92. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation.