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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...

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Autores principales: Khoo, Jun Keng, Montgomery, A. Bruce, Otto, Kelly L., Surber, Mark, Faggian, Jessica, Lickliter, Jason D., Glaspole, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc., publishers 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041323/
https://www.ncbi.nlm.nih.gov/pubmed/30698487
http://dx.doi.org/10.1089/jamp.2018.1507
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author Khoo, Jun Keng
Montgomery, A. Bruce
Otto, Kelly L.
Surber, Mark
Faggian, Jessica
Lickliter, Jason D.
Glaspole, Ian
author_facet Khoo, Jun Keng
Montgomery, A. Bruce
Otto, Kelly L.
Surber, Mark
Faggian, Jessica
Lickliter, Jason D.
Glaspole, Ian
author_sort Khoo, Jun Keng
collection PubMed
description 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.
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spelling pubmed-70413232020-02-26 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 Khoo, Jun Keng Montgomery, A. Bruce Otto, Kelly L. Surber, Mark Faggian, Jessica Lickliter, Jason D. Glaspole, Ian J Aerosol Med Pulm Drug Deliv Original Research 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. Mary Ann Liebert, Inc., publishers 2020-02-01 2020-01-30 /pmc/articles/PMC7041323/ /pubmed/30698487 http://dx.doi.org/10.1089/jamp.2018.1507 Text en © Jun Keng Khoo, et al., 2020. Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Original Research
Khoo, Jun Keng
Montgomery, A. Bruce
Otto, Kelly L.
Surber, Mark
Faggian, Jessica
Lickliter, Jason D.
Glaspole, Ian
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041323/
https://www.ncbi.nlm.nih.gov/pubmed/30698487
http://dx.doi.org/10.1089/jamp.2018.1507
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