title: Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers.
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 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.
authors.affiliation: AstraZeneca Global Medicines Development, Gothenburg, Sweden.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Werkström
authors.affiliation: AstraZeneca Global Medicines Development, Gothenburg, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Prothon
authors.affiliation: AstraZeneca Global Medicines Development, Gothenburg, Sweden.
authors.forename: Ella
authors.initials: E
authors.lastname: Ekholm
authors.affiliation: AstraZeneca Global Medicines Development, Gothenburg, Sweden.
authors.forename: Carin
authors.initials: C
authors.lastname: Jorup
authors.affiliation: Department of Clinical and Experimental Pharmacology, Laboratory Medicines Unit, Lund University, Lund, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Edsbäcker
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D044466:Asian People; D015415:Biomarkers / Q000097:blood / Q000652:urine; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects* / Q000032:analysis / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D007564:Japan / Q000208:ethnology; D008297:Male; D008657:Metabolic Clearance Rate; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D044465:White People; D055815:Young Adult
chemical_list: C587250:2,2,2-trifluoro-N-(1-((1-(4-fluorophenyl)-1H-indazol-5-yl)oxy)-1-(3-methoxyphenyl)-2-propanyl)acetamide; D000081:Acetamides; D000336:Aerosols; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D015507:Drugs, Investigational; D007191:Indazoles; D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone