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Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers
Author(s) -
Werkström Viktoria,
Prothon Susanne,
Ekholm Ella,
Jorup Carin,
Edsbäcker Staffan
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12621
Subject(s) - pharmacokinetics , medicine , pharmacodynamics , inhalation , asthma , population , urine , adverse effect , endocrinology , pharmacology , physiology , anesthesia , environmental health
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 AZD 5423 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, TRAP 5b, 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. AZD 5423, 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.