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

Abstract

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 ¼ 6 active; n ¼ 2 placebo in each cohort) received 25, 50, and 100 mg pirfenidone, respectively. Cohort 4 (NHV) (n ¼ 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 packyear use) (n ¼ 6 active; n ¼ 2 placebo) and Cohort 6 (IPF patients) (n ¼ 6 all active) received 100 mg of pirfenidone. All treatments were administered with an Investigational eFlow Ò 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 ¼ 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 lg/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.

Low-Dose of Intrapulmonary Pirfenidone Improves Human Transforming Growth Factorβ1-Driven Lung Fibrosis

“…Human transforming growth factor (TGF)β1 transgenic (TG) mice were allocated in groups treated with PFD by oral (n 4) or intranasal (n 4) administration and blood samples were drawn from each group on day 1 and day 22. secretion in alveolar epithelial type II cells (Hisatomi et al, 2012;Du et al, 2020). A recent study showing the tolerability of aerosolized PFD in healthy and IPF subjects supports the safety of PFD's intrapulmonary administration (Khoo et al, 2020). The pharmacokinetics results observed in the present study also favor the use of PFD by the intranasal route.…”

“…Previous reports demonstrated that PFD attenuates endoplasmic reticulum stress and mitochondrial dysfunction, inhibits apoptosis, and reduces extracellular matrix proteins' secretion in alveolar epithelial type II cells ( Hisatomi et al, 2012 ; Du et al, 2020 ). A recent study showing the tolerability of aerosolized PFD in healthy and IPF subjects supports the safety of PFD’s intrapulmonary administration ( Khoo et al, 2020 ).…”

Low-Frequency Intrapulmonary Percussive Ventilation Increases Aerosol Penetration in a 2-Compartment Physical Model of Fibrotic Lung Disease

“…Anatomical and physiological alterations of the respiratory system in IPF may result in altered deposition of inhaled aerosols. Similar total lung deposition, as measured by concentrations in bronchoalveolar lavage fluid ( Khoo et al, 2020 ) or planar scintigraphy ( Samuel and Smaldone, 2019 ), can be achieved in IPF patients as compared to healthy subjects. However, planar scintigraphy images suggest that deposition of micrometric aerosols is not homogenous in some IPF patients, in contrast with healthy subjects ( Kanazawa et al, 1993 ; Khoo et al, 2020 ).…”

“…Similar total lung deposition, as measured by concentrations in bronchoalveolar lavage fluid ( Khoo et al, 2020 ) or planar scintigraphy ( Samuel and Smaldone, 2019 ), can be achieved in IPF patients as compared to healthy subjects. However, planar scintigraphy images suggest that deposition of micrometric aerosols is not homogenous in some IPF patients, in contrast with healthy subjects ( Kanazawa et al, 1993 ; Khoo et al, 2020 ). Similarly, deposition of the nanometric aerosol Technegas was patchy and predominated in the upper regions of the lungs, which are typically the less damaged areas in 2 IPF patients ( Watanabe et al, 1995 ).…”

“…Although the total amount of aerosol-delivered drugs may be similar in patients with fibrotic lung disease and healthy controls at the level of the whole organ ( Diaz et al, 2012 ; Khoo et al, 2020 ), imaging studies suggest that inhaled aerosols may mainly deposit into the less-affected regions of the lungs and thus presumably miss their cellular targets ( Kanazawa et al, 1993 ; Watanabe et al, 1995 ). Despite recent demonstration that small aerosol particles (1.5 μm diameter) and polydisperse aerosols should be preferred for IPF patients (“ The Topical Study of Inhaled Drug (Salbutamol), 2019 Delivery in Idiopathic Pulmonary Fibrosis.…”