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

Abstract

IntroductionAZD7594 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.MethodsInhaled 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.ResultsInhaled 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).ConclusionIn 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.

<p>Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review</p>

“… Placebo (q.d.) Oral inhalation DPI Mild to moderate asthmatic (pre-bronchodilator FEV 1 ≥40% and ≤90% of predicted, F E NO ≥25 ppb) 50.8 82.9 0.0 NA 27.3 ≥40.0 and ≤90.0 Lung function, symptom control, PK, PD, and safety 5 Prothon et al, 2019 45 , 46 NCT02645253 Phase I, single-center, randomized, single-blind, placebo-controlled, sequential-group 20 27 AZD7594 200 μg (q.d. ), 400 μg (q.d.…”

“…A Phase I RCT (NCT02645253) investigated the PK and PD of single and repeat doses of AZD7594 200–1600 μg delivered via a DPI in healthy Japanese male subjects. 45 , 46 Plasma exposure indicated dose-proportional PK. 45 , 46 The C max of single doses of AZD7594 200–1600 μg was 56.05–430.8 pmol/L and t max was 0.25–0.50 h. 45 , 46 Only in a few subjects, the terminal t 1/2 was reliably estimated to be 40.0–44.0 h since the investigated drug showed a slow terminal phase and achieved low sustained concentrations over the sampling period.…”

“…45,46 Only multiple doses of AZD7594 1600 μg elicited a partial cortisol suppression compared to placebo, although no reduction in osteocalcin level occurred at any dose. 45,46 AZD7594 58-800 μg induced a rapid increase in plasma concentrations with a mean C max of 36.4-169.7 pmol/L, followed by a rapid decline in plasma concentration and a slow elimination phase. 43,44 The t max was 0.25 h at all doses.…”

“…45,46 Urinary excretion of AZD7594 was considered a negligible elimination pathway since less than 0.02% of unchanged drug was excreted in the urine. 45,46 Only multiple doses of AZD7594 1600 μg elicited a partial cortisol suppression compared to placebo, although no reduction in osteocalcin level occurred at any dose. 45,46 AZD7594 58-800 μg induced a rapid increase in plasma concentrations with a mean C max of 36.4-169.7 pmol/L, followed by a rapid decline in plasma concentration and a slow elimination phase.…”

“…43,44 AZD7594 was safe and well tolerated, and no SAEs were reported in the studies. [43][44][45][46]51,52 AZD7594 is still under investigation for asthma in an ongoing Phase I study. 67 In general, inhaled AZD7594 exerted potent antiinflammatory effects in animal models of pulmonary inflammation.…”