title: Pulmonary Deposition and Elimination of Liposomal Amikacin for Inhalation and Effect on Macrophage Function after Administration in Rats.
abstract: Pulmonary nontuberculous mycobacterial (PNTM) infections represent a treatment challenge. Liposomal amikacin for inhalation (LAI) is a novel formulation currently in development for the treatment of PNTM infections. The pulmonary deposition and elimination of LAI and its effect on macrophage function were evaluated in a series of preclinical studies in healthy rats. The pulmonary deposition of LAI was evaluated in female rats (n = 76) treated with LAI by nebulizer at 10 mg/kg of body weight per day or 90 mg/kg per day for 27 days, followed by dosing of dually labeled LAI (LAI with a lipid label plus an amikacin label) on day 28 with subsequent lung histological and amikacin analyses. In a separate study for assessment of alveolar macrophage function, rats (n = 180) received daily treatment with LAI at 90 mg/kg per day or 1.5% saline over three 30-day treatment periods followed by 30-day recovery periods; phagocytic and Saccharomyces cerevisiae (yeast) killing capabilities and inflammatory mediator release were assessed at the end of each period. LAI demonstrated equal dose-dependent deposition across all lung lobes and regions. Lipid and amikacin labels showed diffuse extracellular colocalization, followed by macrophage uptake and gradual amikacin elimination. Macrophages demonstrated accumulation of amikacin during treatment periods and nearly complete elimination during recovery periods. No evidence of an inflammatory response was seen. No differences in microsphere uptake or yeast killing were seen between LAI-treated and control macrophages. Neither LAI-treated nor control macrophages demonstrated constitutive inflammatory mediator release; however, both showed normal mediator release on lipopolysaccharide stimulation. LAI is readily taken up by macrophages in healthy rats without compromising macrophage function.
authors.affiliation: Insmed Incorporated, Bridgewater, New Jersey, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Malinin
authors.affiliation: Insmed Incorporated, Bridgewater, New Jersey, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Neville
authors.affiliation: Insmed Incorporated, Bridgewater, New Jersey, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Eagle
authors.affiliation: Insmed Incorporated, Bridgewater, New Jersey, USA.
authors.forename: Renu
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Insmed Incorporated, Bridgewater, New Jersey, USA walter.perkins@Insmed.com.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Perkins
mesh_terms: D000280:Administration, Inhalation; D000583:Amikacin / Q000493:pharmacokinetics*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005260:Female; D008081:Liposomes / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D009330:Nebulizers and Vaporizers; D010587:Phagocytosis / Q000187:drug effects; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D000583:Amikacin