Dataset Information

Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator.

ABSTRACT: BACKGROUND:Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/?2-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma. METHODS:This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50-2100??g) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1?s (FEV1) for each treatment period. RESULTS:Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n?=?10, 62.5%) and nasopharyngitis (n?=?7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5?min post-dose). Doses ?200??g resulted in improvements in trough FEV1 (mean change from baseline range 0.186-0.463?L) with sustained bronchodilation for 24-36?h. Plasma concentrations increased in a dose-proportional manner, peaking ~?1?h post-dose, with a derived terminal elimination half-life of 15.96-23.10?h. CONCLUSIONS:In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36?h. TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT02573155.

SUBMITTER: Jimenez E

PROVIDER: S-EPMC7487994 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator.

Jimenez Eulalia E Astbury Carol C Albayaty Muna M Wählby-Hamrén Ulrika U Seoane Beatriz B Villarroel Cristina C Pujol Helena H Bermejo Maria Jesus MJ Aggarwal Ajay A Psallidas Ioannis I

Respiratory research 20200909 Suppl 1

<h4>Background</h4>Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β<sub>2</sub>-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma.<h4>Methods</h4>This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts ...[more]

PMID: 32907576

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Project description:Purpose:The purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor. Materials and methods:Two healthy volunteer, randomized, double-blind, placebo-controlled studies were conducted. In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period. In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 µg or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 µg or placebo once daily (OD). In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 µg or placebo; Part 2, 1,200, 2,000, or 2,400 µg twice daily (BID) or placebo. Modeling and simulation then compared OD and BID dosing via MDDPI. Results:There was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI. CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0-24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0-12 h in Study 2. Bioavailability wa?30% higher with MDDPI than SDDPI. The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration. CHF6001 was well tolerated with no relationship between dose and adverse events. Conclusion:CHF6001 demonstrated a good safety profile. There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition. BID dosing was associated with a better exposure profile.

Dataset Information

Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator.

Publications

Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator.

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