A Randomized, Double-Blinded, Placebo-Controlled, Dose-Escalation Phase 1 Study of Aerosolized Pirfenidone Delivered via the PARI Investigational eFlow Nebulizer in Volunteers and Patients with Idiopathic Pulmonary Fibrosis.

Background: This clinical trial evaluated the pharmacokinetics and safety/tolerability of inhaled pirfenidone solution in volunteers and patients with idiopathic pulmonary fibrosis (IPF). Methods: Forty-four adults in six cohorts consented to receive single doses of a 12.5 mg/mL pirfenidone solution or placebo to assess tolerability and pharmacokinetics. Cohorts 1, 2, and 3 (normal healthy volunteers [NHV]) (n = 6 active; n = 2 placebo in each cohort) received 25, 50, and 100 mg pirfenidone, respectively. Cohort 4 (NHV) (n = 6 all active) received 100 mg of pirfenidone and underwent bronchoalveolar lavage (BAL) to measure epithelial lining fluid (ELF) pirfenidone concentrations. Cohort 5 (prior or current smokers with greater than 20 pack-year use) (n = 6 active; n = 2 placebo) and Cohort 6 (IPF patients) (n = 6 all active) received 100 mg of pirfenidone. All treatments were administered with an Investigational eFlow® Nebulizer System (PARI Pharma GmbH). Serial measures of urine and plasma pirfenidone were collected during the 24-hour postdose in all subjects. Results: Administration time ranged from 1.4 to 2 min/mL. No clinically relevant adverse effects on respiratory rate, spirometry, or oxygenation were observed. Drug-related adverse events were predominantly cough, n = 8/44 (one in IPF cohort), all mild, transient, and not dose limiting. Mean plasma pirfenidone Cmax levels in the 25, 50, 100 mg NHV, 100 mg smoker, and IPF cohorts were 202, 292, 802, 1370, 1016, and 1026 ng/mL, respectively. BAL cohort estimated ELF Cmax was 135.9 ± 54.5 µg/mL. In the BAL and IPF cohorts, 24-hour urine excretion of pirfenidone and metabolites data suggests similar alveolar deposition. Conclusions: Aerosol pirfenidone was well tolerated in normal volunteers, smokers, and IPF patients. High ELF concentrations were achieved in NHV with a 100 mg nebulizer dose. The 100 mg nebulizer dose averaged a 15-fold lower systemic pirfenidone exposure than reported with oral administration of the licensed oral dose.

A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection.

BACKGROUND: Aztreonam lysine for inhalation (AZLI) is being developed for treatment of CF patients with Pseudomonas aeruginosa airway infection. METHODS: This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 and 225 mg AZLI administered BID for 14 days using the eFlow Electronic Nebulizer (Pari Innovative Manufacturers, Inc., Midlothian, VA). Patients were 13 years and older with FEV1>or=40% predicted, chronic P. aeruginosa infection, and had used no anti-pseudomonal antibiotics for 56 days. RESULTS: Of 131 patients screened, 105 received AZLI or placebo. Mean age was 26 years and mean FEV1 percent predicted was 77% at baseline. There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P<0.001). The planned primary analysis, percent change in FEV1 at Day 14, demonstrated no statistically significant difference. Post hoc analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV1, as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group. Adverse events were similar between placebo and AZLI although there was a trend toward increased respiratory symptoms in the 225 mg AZLI group. CONCLUSION: These data support the further development of AZLI and provide information for the design of subsequent studies.