Safety and toxicology of XXXX in propylene glycol after 9-month aerosol exposure to @entity235 .

@entity1 @entity137 @entity235 @entity205 @entity1557
BACKGROUND: @entity205 inhalation solution (CIS) delivered via nebulization is under evaluation for the prevention of chronic rejection post-lung transplant. A 300- @entity1 randomized, controlled clinical trial (CYCLIST) is expected to be completed late in 2011. In support of this trial, a chronic inhalation toxicology study in @entity235 has been completed. METHODS: 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. RESULTS: All @entity235 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 @entity137 associated with exposure to CIS, and the only possible drug-related effect was an observation of benign @entity1557 tissue in the mammary glands of the high-dose female recovery group. Toxicokinetic data showed that @entity205 is initially absorbed rapidly with little drug remaining in lung tissue or blood 24   h after the end of dosing. CONCLUSION: 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 @entity1 are receiving in the CYCLIST trial.
