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Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers

Werkström, Viktoria LU ; Prothon, Susanne; Ekholm, Ella LU ; Jorup, Carin and Edsbäcker, Staffan (2016) In Basic and Clinical Pharmacology and Toxicology 119(6). p.574-581
Abstract

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4β-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished... (More)

AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4β-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus–pituitary–adrenal (HPA) effects appeared to be marginally greater in the Japanese- versus the Caucasian-dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 μg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit–risk ratio may be improved relative to conventional inhaled steroids.

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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Basic and Clinical Pharmacology and Toxicology
volume
119
issue
6
pages
8 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84978287517
ISSN
1742-7835
DOI
10.1111/bcpt.12621
language
English
LU publication?
no
id
14f23ad1-eca5-460e-8075-0f9ad80571e3
date added to LUP
2017-02-22 13:58:43
date last changed
2017-11-12 04:29:47
@article{14f23ad1-eca5-460e-8075-0f9ad80571e3,
  abstract     = {<p>AZD5423 is a selective glucocorticosteroid receptor modulator developed for the inhaled use in asthma and COPD. This study reports the initial, first-in-man, single and repeat dose-escalating studies in healthy male individuals, including one cohort of male Japanese individuals. Inhaled, nebulized AZD5423 was safe and well tolerated up to and including the highest doses tested for up to 2 weeks of once-daily treatment. Plasma exposure suggested dose-proportional pharmacokinetics and dose-related effects on 24-hr plasma and urine cortisol. There were no or marginal effects on other biomarkers tested (osteocalcin, TRAP5b, DHEA-S and 4β-OH-cholesterol). No clinically relevant differences in safety or pharmacokinetics could be distinguished between the two study populations, although hypothalamus–pituitary–adrenal (HPA) effects appeared to be marginally greater in the Japanese- versus the Caucasian-dominant study population. AZD5423, inhaled via nebulization, can be used in healthy individuals at doses of at least 300 μg for 2 weeks. The effects on the HPA axis reported herein, together with efficacy data reported elsewhere, indicate that benefit–risk ratio may be improved relative to conventional inhaled steroids.</p>},
  author       = {Werkström, Viktoria and Prothon, Susanne and Ekholm, Ella and Jorup, Carin and Edsbäcker, Staffan},
  issn         = {1742-7835},
  language     = {eng},
  month        = {12},
  number       = {6},
  pages        = {574--581},
  publisher    = {Wiley-Blackwell},
  series       = {Basic and Clinical Pharmacology and Toxicology},
  title        = {Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers},
  url          = {http://dx.doi.org/10.1111/bcpt.12621},
  volume       = {119},
  year         = {2016},
}