PMID- 32907575 OWN - NLM STAT- MEDLINE DCOM- 20210721 LR - 20221207 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 21 IP - Suppl 1 DP - 2020 Sep 9 TI - Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies. PG - 212 LID - 10.1186/s12931-020-01474-1 [doi] LID - 212 AB - BACKGROUND: Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and beta(2-)adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma. METHODS: These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300 mug to 600 mug to 900 mug. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed. RESULTS: Twenty-four volunteers completed each study (navafenterol, n = 6; placebo, n = 2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n = 2; navafenterol 900 mug; n = 3) in study A and diarrhoea (placebo, n = 1; navafenterol 300 mug, n = 2; navafenterol 900 mug, n = 3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers. CONCLUSIONS: Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development. TRIAL REGISTRATION: ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov . FAU - Balaguer, Victor AU - Balaguer V AD - Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. FAU - Albayaty, Muna AU - Albayaty M AD - the Early Phase Clinical Unit, PAREXEL International GmbH, Harrow, UK. FAU - Jimenez, Eulalia AU - Jimenez E AD - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Barcelona, Spain. FAU - Wahlby-Hamren, Ulrika AU - Wahlby-Hamren U AD - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden. FAU - Astbury, Carol AU - Astbury C AD - Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. FAU - Seoane, Beatriz AU - Seoane B AD - Biometrics and Information Sciences, Late Stage Development, BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. FAU - Malice, Marie-Pierre AU - Malice MP AD - Early Biostats and Statistical Innovation, Data Science and AI, BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain. FAU - Lei, Alejhandra AU - Lei A AD - Patient Safety RIA, Chief Medical Office, R&D, AstraZeneca, Barcelona, Spain. FAU - Aggarwal, Ajay AU - Aggarwal A AD - Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA. FAU - Psallidas, Ioannis AU - Psallidas I AUID- ORCID: 0000-0001-7284-0111 AD - Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK. ioannis.psallidas@astrazeneca.com. LA - eng SI - ClinicalTrials.gov/NCT03159442 SI - ClinicalTrials.gov/NCT02814656 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial DEP - 20200909 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Adrenergic beta-2 Receptor Agonists) RN - 0 (Bronchodilator Agents) RN - 0 (Muscarinic Antagonists) RN - 0 (Quinolines) RN - 0 (Triazoles) RN - U29GY32XJ4 (AZD-8871) SB - IM MH - Administration, Inhalation MH - Adrenergic beta-2 Receptor Agonists/*administration & dosage/adverse effects/pharmacokinetics MH - Adult MH - Asian People MH - Bronchodilator Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Healthy Volunteers MH - Humans MH - Japan/ethnology MH - London MH - Male MH - Middle Aged MH - Muscarinic Antagonists/*administration & dosage/adverse effects/pharmacokinetics MH - Quinolines/*administration & dosage/adverse effects/pharmacokinetics MH - Single-Blind Method MH - Triazoles/*administration & dosage/adverse effects/pharmacokinetics PMC - PMC7488005 OTO - NOTNLM OT - Bronchodilator OT - COPD OT - Dual-pharmacology muscarinic receptor antagonist beta2-adrenoceptor agonist OT - MABA OT - Pharmacokinetics OT - Safety COIS- VB was an employee of AstraZeneca at the time these studies were conducted and is now a current employee of IQVIA. LJ, UW-H, CA, BS, AL and IP are employees of AstraZeneca, and may own stock or stock options. AA was an employee of AstraZeneca at the time these studies were conducted and is now a current employee of Eloxx Pharmaceuticals. M-PM was a contractor to AstraZeneca at the time these studies were conducted. MA is an employee of PAREXEL. AstraZeneca provided funding to PAREXEL for the conduct of these studies. EDAT- 2020/09/11 06:00 MHDA- 2021/07/22 06:00 PMCR- 2020/09/09 CRDT- 2020/09/10 05:26 PHST- 2020/06/11 00:00 [received] PHST- 2020/07/27 00:00 [accepted] PHST- 2020/09/10 05:26 [entrez] PHST- 2020/09/11 06:00 [pubmed] PHST- 2021/07/22 06:00 [medline] PHST- 2020/09/09 00:00 [pmc-release] AID - 10.1186/s12931-020-01474-1 [pii] AID - 1474 [pii] AID - 10.1186/s12931-020-01474-1 [doi] PST - epublish SO - Respir Res. 2020 Sep 9;21(Suppl 1):212. doi: 10.1186/s12931-020-01474-1.