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

<b><i>Background:</i></b> This clinical trial evaluated the pharmacokinetics and safety/tolerability of inhaled pirfenidone solution in volunteers and patients with idiopathic pulmonary fibrosis (IPF). <b><i>Methods:</i></b> 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]) (<i>n</i> = 6 active; <i>n</i> = 2 placebo in each cohort) received 25, 50, and 100 mg pirfenidone, respectively. Cohort 4 (NHV) (<i>n</i> = 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) (<i>n</i> = 6 active; <i>n</i> = 2 placebo) and Cohort 6 (IPF patients) (<i>n</i> = 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. <b><i>Results:</i></b> 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, <i>n</i> = 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. <b><i>Conclusions:</i></b> 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.