Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers
Received 11 May 2019
Accepted for publication 28 August 2019
Published 12 November 2019 Volume 2019:13 Pages 3845—3853
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Cristiana Tanase
Susanne Prothon,1 Ulrika Wählby Hamrén,1 Ulrika Tehler,2 Esther Yoon,3 Henrik Forsman,4 Cecilia Arfvidsson,5 Ajay Aggarwal,6 Yingxue Chen7
1Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 2Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 3Early Phase Clinical Unit, PAREXEL, Glendale, CA, USA; 4Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Clinical Sample and Bioanalytical Science, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden; 6Research and Early Development, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA; 7Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Boston, MA, USA
Correspondence: Susanne Prothon
Clinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, Sweden
Introduction: AZD7594 is a non-steroidal, selective, glucocorticoid receptor modulator (SGRM), currently in development for the treatment of asthma and chronic obstructive pulmonary disease. This paper reports a randomized placebo-controlled dose escalation study in healthy Japanese male subjects.
Methods: Inhaled AZD7594 was administered as one single dose at day 1 (day 1–4), with subsequent multiple daily doses (day 5–16) via a multiple-dose dry powder inhaler for 12 days of once-daily treatment. At each dose level, subjects were randomized to AZD7594 (n=7) or placebo (n=2). The safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 were evaluated.
Results: Inhaled AZD7594 was safe and well tolerated up to and including the highest dose 1600 μg tested. Plasma exposure suggested dose-proportional PK. The urinary excretion of AZD7594 was negligible (<0.02%). Dose-related effects were observed for 24 hrs plasma cortisol; however, significant cortisol suppression (25%) was only seen at the highest dose level following multiple doses. There were no or only marginal effects on other biomarkers tested (dehydroepiandrosterone sulfate [DHEA-S] and osteocalcin).
Conclusion: In conclusion, the early clinical evaluation of inhaled AZD7594 suggests that this novel SGRM is well tolerated in the dose range investigated and also in a Japanese population. It shows dose-proportional plasma exposure, moderate accumulation and has limited impact on systemic markers of glucocorticoid activity.
Keywords: systemic activity, AZD7594, SGRM, Japanese, healthy subjects, pharmacokinetics, pharmacodynamics, glucocorticoid receptor modulator
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