The Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide 400 μg Administered by Inhalation as Single and Multiple (Twice Daily) Doses in Healthy Chinese Participants

Abstract

Purpose

To date, aclidinium pharmacokinetic (PK) studies have focused on Caucasian populations, and no data are available for Chinese populations. We aimed to characterize the PK and safety profile of aclidinium and its metabolites (LAS34823 and LAS34850) following single and multiple (twice-daily; BID) dosing in healthy Chinese participants, and to compare PK data between Chinese and Caucasian populations.

Materials and methods

In this Phase I, open-label study (NCT03276052), healthy participants from a single site in China received aclidinium bromide 400 µg via a dry powder inhaler. The Day 1 single dose was followed by a washout period of 96 hours. On Days 5 through 8, participants received BID doses.

Results

Twenty healthy Chinese participants, aged 18–45 years, were enrolled. Aclidinium absorption was rapid (median time to maximum concentration [t_max] 0.08 hours post-dose following single/multiple doses). LAS34823 had a similar median t_max of 0.08 hours, whereas LAS34850 t_max occurred later (median 2.50–3.00 hours). Aclidinium, LAS34823, and LAS34850 concentrations declined in a bi-phasic manner; geometric mean half-life was 13.5 hours (single dosing) and 21.4 hours (multiple dosing), while steady state was generally achieved after 5 days’ continuous dosing. Area under the concentration–time curve during a dosage interval (AUC_τ) metabolite to parent ratios for LAS34823 were 2.6 (Day 1) and 2.9 (Day 9), while LAS34850 had ratios of 136.0 and 94.8, respectively. Aclidinium accumulation occurred after 5 days of BID dosing (LS mean accumulation ratio for AUC_τ Day 9/Day 1: 214.1% [90% CI, 176.5, 259.6]); LAS34823 accumulation was similar, while LAS34850 accumulation was lower. Between-participant exposure variability was moderate to high for aclidinium and LAS34823, and low for LAS34850.

Conclusion

Single and multiple doses of aclidinium were well tolerated in healthy Chinese participants. The safety profile of and exposure to aclidinium was consistent with previous studies conducted in Caucasian populations.

Keywords:

• aclidinium bromide
• bronchodilator
• China
• chronic obstructive pulmonary disease
• pharmacokinetics
• safety

Data Sharing Statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. 

Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. AstraZeneca Vivli member page is also available outlining further details: https://vivli.org/ourmember/astrazeneca/.

Ethics Approval

The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation Good Clinical Practice Guidelines and conformed with local regulatory requirements. The site Ethics Committee (Ethics Committees on Clinical Trial, West China Hospital of Sichuan University; No. 37 Guoxue Xiang Wu Hou District Chengdu 610041) reviewed and approved the final protocol, any amendments, and the informed consent documentation.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Acknowledgments

The authors would like to acknowledge the participants who took part in the study and their families, as well as the principal investigators from each country for their contributions. Medical writing support, under the direction of the authors, was provided by Richard Knight, PhD, and Bethan Hahn, PhD, of CMC Connect, a division of IPG Health Medical Communications, funded by AstraZeneca, in accordance with Good Publication Practice (GPP 2022) guidelines.¹⁷

Disclosure

Weimin Li does not have any competing interests to declare in this work. Sami Daoud, Roopa Trivedi, Pradeep Lukka, Eulalia Jimenez and Eduard Molins are employees of AstraZeneca and may hold stock. Catherine Stewart is an employee of Plus Project Partnership and was an employee of Phastar at the time of this study. Pranob Bharali is an employee of AstraZeneca who does not hold stock. Esther Garcia-Gil is a former employee of AstraZeneca. The authors report no other conflicts of interest in this work.

Additional information

Funding

The study was funded by AstraZeneca.