Administration of Cyclosporine by Inhalation: A Feasibility Study in Beagle Dogs

Abstract

Acute rejection with perivascular and interstitial reaction and chronic rejection with obliterative bronchiolitis are problems in some patients with transplanted lungs who are being administered cyclosporine orally. Levels of orally administered cyclosporine required to provide adequate immunosuppression to prevent rejection of lung allografts sometimes also elicit nephrotoxic responses. Since the lung is the target organ for immunosuppression, delivery of cyclosporine directly to the lung may enhance the effectiveness of a given dose of cyclosporine in prevention of chronic lung rejection without increasing the risk of renal damage. Five dogs were each treated with inhaled, oral, and intravenous cyclosporine, aerosol vehicle (ethyl alcohol), and no treatment, over a five-week period. One treatment per week was given to each dog. A radiolabel, 99mTc was included in the cyclosporine aerosol to allow scintigraphy of lung distribution of the aerosol and to determine the amount of aerosol deposited. The blood plasma concentrations of cyclosporine were approximately the same at 4 and 24 hours for all routes of administration. Aerosol distribution in the lung appeared uniform based on 99mTc scintigrams. In a second study, two dogs inhaled cyclosporine once a day for five days, two dogs inhaled the aerosol vehicle, and one dog was not treated. No evidence of acute lung injury was found based on cell counts, total protein, alkaline phosphatase, or lactic dehydrogenase levels in the bronchoalveolar lavage fluid at 24 hours after one or five administrations of cyclosporine. These data indicate that cyclosporine administered by aerosol either once or five times was distributed throughout the lung and absorbed into the blood without producing an acute inflammatory reaction in the lung, and further suggest that cyclosporine may be given by inhalation to lung transplant recipients without untoward health effects.