title: Safety and systemic absorption of pulmonary delivered human IFN-beta1a in the nonhuman primate: comparison with subcutaneous dosing.
abstract: Safety and bioavailability of pulmonary delivered interferon-beta 1a (IFN-beta1a, AVONEX, Biogen, Inc., Cambridge, MA) was evaluated in the nonhuman primate. Pulmonary bioavailability following intratracheal (i.t.) instillation of 50 microg/kg IFN-beta1a to rhesus macaques was approximately 10%. To evaluate pulmonary safety, IFN-beta1a was administered intrabronchially to rhesus and cynomolgus macaques at a dose of 60 microg/dose one, three, or seven times per week for 4 weeks. At scheduled termination, lungs were evaluated for gross and histomorphologic changes. IFN-beta1a 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-beta1a induced mild to moderate eosinophilic alveolitis, considered possibly an isolated type I hypersensitivity response to HSA or IFN-beta1a. 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-beta1a is safe and that the pulmonary route of administration is a possible alternate route for the systemic delivery of IFN-beta1a.
authors.affiliation: Biogen, Inc., Cambridge, MA 02142, USA. pauline_martin@biogen.com
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Martin
authors.forename: Sujata
authors.initials: S
authors.lastname: Vaidyanathan
authors.forename: Joan
authors.initials: J
authors.lastname: Lane
authors.forename: Mark
authors.initials: M
authors.lastname: Rogge
authors.forename: Nancy
authors.initials: N
authors.lastname: Gillette
authors.forename: Birgit
authors.initials: B
authors.lastname: Niggemann
authors.forename: James
authors.initials: J
authors.lastname: Green
mesh_terms: D000042:Absorption; D000818:Animals; D000906:Antibodies / Q000032:analysis; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007322:Instillation, Drug; D016899:Interferon-beta / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D019798:Neopterin / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D019798:Neopterin; D016899:Interferon-beta