Safety and Toxicology of Cyclosporine in Propylene Glycol after 9-Month Aerosol Exposure to Beagle Dogs

Abstract

Cyclosporine inhalation solution (CIS) delivered via nebulization is under evaluation for the prevention of chronic rejection post-lung transplant. A 300-patient randomized, controlled clinical trial (CYCLIST) is expected to be completed late in 2011. In support of this trial, a chronic inhalation toxicology study in dogs has been completed. To mimic the clinical setting, animals (four/sex/dose plus two/sex/dose in the control and high dose recovery groups) were exposed to aerosolized CIS, via nose-only exposure, three times per week for 9 months at targeted inhaled doses of 0 (air), 4, 12, and 24 mg/kg. In addition, the potential for persistence or reversibility of any toxic effects were assessed after a 6-week recovery period. The toxicological endpoints included clinical observations, body-weight, food consumption, toxicokinetics, clinical chemistry, and histopathology. All dogs receiving CIS completed the study with the only consistent observations being excessive salivation and changes in minute ventilation. There was no limiting lung or systemic toxicity associated with exposure to CIS, and the only possible drug-related effect was an observation of benign fibroadenoma tissue in the mammary glands of the high-dose female recovery group. Toxicokinetic data showed that cyclosporine is initially absorbed rapidly with little drug remaining in lung tissue or blood 24 h after the end of dosing. The study supports the pulmonary and systemic safety of aerosolized CIS at expected lung dose levels/kg of up to 12 times greater than the average dose patients are receiving in the CYCLIST trial.