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An Ascending, Repeat-Dose Safety and Tolerability Study of AZD8871 a Novel, Dual-Acting Bronchodilator in Healthy Volunteers
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A4771 - An Ascending, Repeat-Dose Safety and Tolerability Study of AZD8871 a Novel, Dual-Acting Bronchodilator in Healthy Volunteers
Author Block: C. Astbury1, L. Jimenez2, B. Seoane3, C. Villarroel1, M. Albayaty4, V. Balaguer5, A. Lei6, A. Aggarwal7; 1Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 2Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 3Biometrics and Information Sciences, Global Medicines Development, AstraZeneca, Barcelona, Spain, 4Early Phase Clinical Unit, PAREXEL International, London, United Kingdom, 5RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 6Patient Safety RIA, GRAPSQA, GMD Development, AstraZeneca, Barcelona, Spain, 7RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, United States.
AZD8871 is a novel inhaled long acting dual pharmacology muscarinic antagonist/ β2 adrenoceptor agonist (MABA) bronchodilator for COPD/asthma. In this study, the safety, tolerability and pharmacokinetics of AZD8871 following repeat-dose administration were tested for the first time.
3 cohorts of 8 healthy male volunteers each received a single dose of AZD8871 or placebo on Day 1, followed by a 3-day washout and once daily dosing on Days 5-16. In each cohort, 6 subjects received 300, 600 and 900 µg and 2 received placebo. All treatments were administered by a dry-powder inhaler.
There were no serious AEs and no stopping criteria were met. The most frequent adverse events (AE) was headache (25% subjects). No dose-response was observed with any specific AE. No clinically relevant laboratory, ECG or vital signs results were reported except for dose-dependent effect on heart rate registered by digital ECGt on Day 16. No safety concerns were raised.
Dosing remained below pre-specified human exposure limits and the maximum tolerated dose was not reached. AZD8871 was rapidly absorbed (median tmax 1.5h -1.52h). Dose proportionality was observed and steady state was achieved within 8 days of repeat dosing. Accumulation after multiple dosing of AZD8871 was seen for AUCτ (Rac 1.4-1.7) and to a minor extent for Cmax (Rac 1.02-1.12). Mean terminal elimination half-life after multiple dosing ranged 62-79h.
The results support further clinical development of AZD8871.
Author Block: C. Astbury1, L. Jimenez2, B. Seoane3, C. Villarroel1, M. Albayaty4, V. Balaguer5, A. Lei6, A. Aggarwal7; 1Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 2Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 3Biometrics and Information Sciences, Global Medicines Development, AstraZeneca, Barcelona, Spain, 4Early Phase Clinical Unit, PAREXEL International, London, United Kingdom, 5RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Barcelona, Spain, 6Patient Safety RIA, GRAPSQA, GMD Development, AstraZeneca, Barcelona, Spain, 7RIA TMU, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Boston, MA, United States.
AZD8871 is a novel inhaled long acting dual pharmacology muscarinic antagonist/ β2 adrenoceptor agonist (MABA) bronchodilator for COPD/asthma. In this study, the safety, tolerability and pharmacokinetics of AZD8871 following repeat-dose administration were tested for the first time.
3 cohorts of 8 healthy male volunteers each received a single dose of AZD8871 or placebo on Day 1, followed by a 3-day washout and once daily dosing on Days 5-16. In each cohort, 6 subjects received 300, 600 and 900 µg and 2 received placebo. All treatments were administered by a dry-powder inhaler.
There were no serious AEs and no stopping criteria were met. The most frequent adverse events (AE) was headache (25% subjects). No dose-response was observed with any specific AE. No clinically relevant laboratory, ECG or vital signs results were reported except for dose-dependent effect on heart rate registered by digital ECGt on Day 16. No safety concerns were raised.
Dosing remained below pre-specified human exposure limits and the maximum tolerated dose was not reached. AZD8871 was rapidly absorbed (median tmax 1.5h -1.52h). Dose proportionality was observed and steady state was achieved within 8 days of repeat dosing. Accumulation after multiple dosing of AZD8871 was seen for AUCτ (Rac 1.4-1.7) and to a minor extent for Cmax (Rac 1.02-1.12). Mean terminal elimination half-life after multiple dosing ranged 62-79h.
The results support further clinical development of AZD8871.
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