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.
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands. g.s.zijlstra@rug.nl
Gerrit S
GS
Zijlstra
Joske
J
Wolting
Jochum
J
Prop
Arjen H
AH
Petersen
Wouter L J
WL
Hinrichs
Donald R A
DR
Uges
Huib A M
HA
Kerstjens
Wim
W
van der Bij
Henderik W
HW
Frijlink
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D011208:Powders; D051381:Rats; D011919:Rats, Inbred Strains
D007166:Immunosuppressive Agents; D011208:Powders; D016572:Cyclosporine