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

Abstract

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

Acknowledgments

We thank the volunteers who participated in this study, and the former AstraZeneca colleagues Hong-Lin Su for statistical planning and evaluation and Mats Bjersing for study coordination. This study was conducted in collaboration with PAREXEL. Editorial assistance was provided by David Candlish and Sophieanne Wastling of inScience Communications, Springer Healthcare Ltd, UK, which was funded by AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3). This study was funded by AstraZeneca.

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.

Abbreviations

AUC, area under the curve; DHEA-S, dehydroepiandrosterone sulfate; HPA, hypothalamic-pituitary-adrenal axis; ICS, inhaled corticosteroids; MAD, multiple ascending dose; PK, pharmacokinetics; PD, pharmacodynamics; SAD, single ascending dose; SGRM, selective glucocorticoid receptor modulator.

Disclosure

SP, UT, YC, HF, CA, AA, and UWH are all current or former employees of AstraZeneca. EY is an employee of PAREXEL. AstraZeneca provided funding to PAREXEL for the conduct of this study. SP owns shares in AstraZeneca. UT reports personal fees from AstraZeneca, during the conduct of the study and owns shares in AstraZeneca. HF owns shares in AstraZeneca. The authors report no other conflicts of interest in this work.