Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study.
BACKGROUND
With regard to limiting the systemic effects of cyclosporine A and obtaining better control of acute pulmonary allograft rejection, local immunosuppressive therapy with aerosolized cyclosporine A seems of interest. Given the in situ immunologic mechanisms of acute rejection, as well as the anatomic structure of the lung, this therapy is feasible as previously described by others. The aim of our study is to determine the pharmacokinetic parameters of nebulized cyclosporine A and the best modalities of administration.


METHODS
In a pharmacokinetic study, the cyclosporine A was given either by intramuscular injection (10 mg/kg) or by aerosol at 10 and 25 mg/kg doses; 70 rats were killed at 25 and 50 minutes and 2, 4, 6, 8, 12, 24, or 48 hours after cyclosporine A administration. Cyclosporine A levels were measured in whole blood and in the lung. The areas under the concentration time curves were determined. Twenty-four lung transplantations were then performed. The rats were killed on postoperative day 9. Acute rejection was scored on a scale of 0 to 4, and cyclosporine A trough levels were measured in the lung and in the blood.


RESULTS
With a jet nebulizer, the mass median aerodynamic diameter was 2.5 microns, with a standard geometric deviation of 2.3. In blood, the area under the concentration curve was greater for intramuscular (80.6 ng.hr/ml) than for aerosol administrations at 10 (15.1 ng.hr/ml) and 25 mg/kg (41.0 ng.hr/ml) doses. In the lungs, the area under the concentration curve was greater for the aerosol route at 25 mg/kg doses (588 ng.hr/mg) than for the low-dose (200 ng.hr/mg) or intramuscular administration (200 ng.hr/mg). The lung targeting index of cyclosporine A (ratio area under the concentration curve-lungs/area under the concentration curve-blood) was greater for both aerosol administrations than for the intramuscular route. In the study of the prevention of acute rejection, rats without immunosuppression (n = 6), rats receiving daily doses of cyclosporine A intramuscularly (10 mg/kg), and rats with aerosolized cyclosporine A daily (10 and 25 mg/kg/day) showed mean grades of acute rejection of, respectively, 4, 2.03 +/- 0.27, 2.33 +/- 0.52, and 2.17 +/- 0.46. The deposition of nebulized cyclosporine A was lower in transplanted than in native lung.


CONCLUSIONS
Nebulized cyclosporine A allows better pulmonary concentration than intramuscular administration, and results in lower systemic levels. Prevention of acute rejection is as good with aerosolized cyclosporine A as with intramuscular cyclosporine A. This first pharmacokinetic study of nebulized cyclosporine A could lead to clinical applications.
Blot
F
F
Department of Pneumology, CMC Foch, Suresnes, France.
Tavakoli
R
R
Sellam
S
S
Epardeau
B
B
Faurisson
F
F
Bernard
N
N
Becquemin
M H
MH
Frachon
I
I
Stern
M
M
Pocidalo
J J
JJ
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007273:Injections, Intramuscular; D008168:Lung / Q000276:immunology / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D000336:Aerosols; D007166:Immunosuppressive Agents; D016572:Cyclosporine