Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers

• Main Authors: Prothon S, Wählby Hamrén U, Tehler U, Yoon E, Forsman H, Arfvidsson C, Aggarwal A, Chen Y
• Format: Article
• Language: English
• Published: Dove Medical Press 2019-11-01
• Series: Drug Design, Development and Therapy
• Subjects: systemic activity; azd7594; sgrm; japanese; healthy subjects; pharmacokinetics; pharmacodynamics; glucocorticoid receptor modulator
• Online Access: https://www.dovepress.com/safety-pharmacokinetics-and-pharmacodynamics-of-the-selective-glucocor-peer-reviewed-article-DDDT
• ISSN: 1177-8881

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, USACorrespondence: Susanne ProthonClinical Pharmacology, ADME, and AI, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Pepparedsleden 1, Mölndal 431 83, SwedenEmail [e-mail]: 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