Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety
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RESEARCH
Open Access
Navafenterol (AZD8871) in patients with mild asthma: a randomised placebocontrolled phase I study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator Eulalia Jimenez1*, Carol Astbury2, Muna Albayaty3, Ulrika Wählby-Hamrén4, Beatriz Seoane5, Cristina Villarroel6, Helena Pujol2, Maria Jesus Bermejo7, Ajay Aggarwal2 and Ioannis Psallidas8
Abstract Background: Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/β2adrenoceptor 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 μg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from predose 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 treatmentemergent 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 μg 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 doseproportional 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. (Continued on next page)
* Correspondence: [email protected] 1 Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, 08020 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not
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