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

Zijlstra, G. S., Wolting, J., Prop, J., Petersen, A. H., Hinrichs, W. L. J., Uges, D. R. A., Kerstjens, H. A. M., van der Bij, W. & Frijlink, H. W., 1-May-2009, In : The Journal of Heart and Lung Transplantation. 28, 5, p. 486-492 7 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)486-492
Number of pages7
JournalThe Journal of Heart and Lung Transplantation
Volume28
Issue number5
Publication statusPublished - 1-May-2009

    Keywords

  • cyclosporin A, animal experiment, animal model, animal tissue, area under the curve, article, controlled study, drug blood level, drug dose comparison, drug efficacy, drug formulation, drug half life, drug tissue level, graft rejection, histopathology, lung graft rejection, lung transplantation, lung ventilation, male, nonhuman, postoperative period, priority journal, rat, scoring system, X ray picture

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