Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers
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 P...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2019-11-01
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| Series: | Drug Design, Development and Therapy |
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| Online Access: | https://www.dovepress.com/safety-pharmacokinetics-and-pharmacodynamics-of-the-selective-glucocor-peer-reviewed-article-DDDT |
| _version_ | 1818939120783720448 |
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| author | Prothon S Wählby Hamrén U Tehler U Yoon E Forsman H Arfvidsson C Aggarwal A Chen Y |
| author_facet | Prothon S Wählby Hamrén U Tehler U Yoon E Forsman H Arfvidsson C Aggarwal A Chen Y |
| author_sort | Prothon S |
| collection | DOAJ |
| description | 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 susanne.prothon@astrazeneca.comIntroduction: 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 |
| first_indexed | 2024-12-20T06:18:42Z |
| format | Article |
| id | doaj.art-a49a3bf448b94b4f994acb242d815fd0 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-20T06:18:42Z |
| publishDate | 2019-11-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-a49a3bf448b94b4f994acb242d815fd02022-12-21T19:50:28ZengDove Medical PressDrug Design, Development and Therapy1177-88812019-11-01Volume 133845385349711Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteersProthon SWählby Hamrén UTehler UYoon EForsman HArfvidsson CAggarwal AChen YSusanne 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 susanne.prothon@astrazeneca.comIntroduction: 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 modulatorhttps://www.dovepress.com/safety-pharmacokinetics-and-pharmacodynamics-of-the-selective-glucocor-peer-reviewed-article-DDDTsystemic activityazd7594sgrmjapanesehealthy subjectspharmacokineticspharmacodynamicsglucocorticoid receptor modulator |
| spellingShingle | Prothon S Wählby Hamrén U Tehler U Yoon E Forsman H Arfvidsson C Aggarwal A Chen Y Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers Drug Design, Development and Therapy systemic activity azd7594 sgrm japanese healthy subjects pharmacokinetics pharmacodynamics glucocorticoid receptor modulator |
| title | Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers |
| title_full | Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers |
| title_fullStr | Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers |
| title_full_unstemmed | Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers |
| title_short | Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD7594, following inhalation in healthy Japanese volunteers |
| title_sort | safety pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator azd7594 following inhalation in healthy japanese volunteers |
| topic | systemic activity azd7594 sgrm japanese healthy subjects pharmacokinetics pharmacodynamics glucocorticoid receptor modulator |
| url | https://www.dovepress.com/safety-pharmacokinetics-and-pharmacodynamics-of-the-selective-glucocor-peer-reviewed-article-DDDT |
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