Safety and Systemic Absorption of Pulmonary Delivered Human IFN- β 1a in the Nonhuman Primate: Comparison with Subcutaneous Dosing

Abstract

Safety and bioavailability of pulmonary delivered interferon-β 1a (IFN-β1a, AVONEX^®, Biogen, Inc., Cambridge, MA) was evaluated in the nonhuman primate. Pulmonary bioavailability following intratracheal (i.t.) instillation of 50 μg/kg IFN-β1a to rhesus macaques was approximately 10%. To evaluate pulmonary safety, IFN-β1a was administered intrabronchially to rhesus and cynomolgus macaques at a dose of 60 μg/dose one, three, or seven times per week for 4 weeks. At scheduled termination, lungs were evaluated for gross and histomorphologic changes. IFN-β1a or vehicle (human serum albumin [HSA] in phosphate-buffered saline [PBS]) treatment resulted in minimal to mild subchronic alveolitis, located primarily near the instillation sites. These responses were considered nonspecific and consistent with either instillation of a foreign protein or minor injury associated with the instillation procedure. In one rhesus macaque treated every day for 4 weeks, IFN-β1a induced mild to moderate eosinophilic alveolitis, considered possibly an isolated type I hypersensitivity response to HSA or IFN-β1a. Partial resolution of pulmonary lesions was seen in all recovery animals killed 2 weeks after cessation of treatment. In conclusion, this study shows that pulmonary administration of human IFN-β1a is safe and that the pulmonary route of administration is a possible alternate route for the systemic delivery of IFN-β1a.