title: Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety.
abstract: Aerosolized antibiotics are associated with a high treatment burden that can result in non-adherence to chronic therapy. We evaluated the pharmacokinetics (PK) and safety of tobramycin inhalation powder (TIP), a novel dry-powder formulation designed to deliver a high payload of tobramycin topically to the lungs for management of chronic Pseudomonas aeruginosa infections. This was a multi-center, open-label, sequential-cohort, single-dose, dose-escalation study using the standard 300 mg dose of tobramycin solution for inhalation (TSI) as an active control. Subjects were randomized to TIP or TSI in a 3:1 ratio in each of five cohorts. Measurements included serum and sputum tobramycin concentrations, administration time, serum chemistries, acute change in lung function, and adverse events (AEs). Out of 90 randomized subjects, 86 had data for safety analysis; and 84 had data for PK analysis. Serum tobramycin PK profiles were similar for TIP and TSI. Four capsules of 28 mg TIP (total tobramycin dose 112 mg) produced comparable systemic exposure to 300 mg TSI, in less than one-third the administration time. The most common AEs associated with TIP were cough (20%) and dysgeusia (17%). TIP allows for faster and more efficient pulmonary delivery of tobramycin than TSI and has a safety profile that supports continued clinical investigation. The increased rate of local respiratory tract irritation noted with TIP is not unexpected with a high-payload powder formulation. The development of dry powder inhaled antibiotics may represent an important advance in the treatment of chronic lung infections.
authors.affiliation: Nemours Children's Clinic, Orlando, Florida 32806, USA. dgeller@nemours.org
authors.forename: David E
authors.initials: DE
authors.lastname: Geller
authors.forename: Michael W
authors.initials: MW
authors.lastname: Konstan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Smith
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Noonberg
authors.forename: Carol
authors.initials: C
authors.lastname: Conrad
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D003371:Cough / Q000139:chemically induced; D003550:Cystic Fibrosis / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004408:Dysgeusia / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D009894:Opportunistic Infections / Q000150:complications / Q000188:drug therapy; D011208:Powders; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa; D013183:Sputum / Q000737:chemistry; D014031:Tobramycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D011208:Powders; D014031:Tobramycin