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.

Efficacy and Tolerability of an Inhaled Selective Glucocorticoid Receptor Modulator – AZD5423 – in Chronic Obstructive Pulmonary Disease Patients: Phase II Study Results

“…However, in a PK trial in healthy individuals, the Turbuhaler powder formulation of AZD5423 performed as expected . Also in the present study, the plasma concentration data of AZD5423 versus time were similar to the dose‐normalized plasma concentrations of AZD5423 found in healthy individuals when the PK of AZD5423 was studied over a wide dose range . In addition, plasma cortisol suppression was what would have been expected from the previous tolerability trial: In the multiple ascending dose study in healthy individuals, plasma cortisol was significantly suppressed by AZD5423 versus placebo (29% suppression) at 375 μg lung‐deposited dose via nebulizer, while no suppression could be distinguished at doses below 300 μg .…”

“…Also in the present study, the plasma concentration data of AZD5423 versus time were similar to the dose‐normalized plasma concentrations of AZD5423 found in healthy individuals when the PK of AZD5423 was studied over a wide dose range . In addition, plasma cortisol suppression was what would have been expected from the previous tolerability trial: In the multiple ascending dose study in healthy individuals, plasma cortisol was significantly suppressed by AZD5423 versus placebo (29% suppression) at 375 μg lung‐deposited dose via nebulizer, while no suppression could be distinguished at doses below 300 μg . In the present study, a suppression of 16% was observed at 12 weeks following 404 μg predicted lung‐deposited dose of AZD5423 via Turbuhaler (corresponding to 800 μg daily delivered dose).…”

“…In the current trial, AZD5423 was provided as a powder aerosol and delivered via Turbuhaler. Previous clinical safety and efficacy studies with this compound used nebulizer suspensions . However, in a PK trial in healthy individuals, the Turbuhaler powder formulation of AZD5423 performed as expected .…”

“…To evaluate the effect of AZD5423 on the hypothalamus pituitary adrenal (HPA) axis, the primary variable of interest was the AUC of 24‐hr plasma cortisol levels. The plasma cortisol assay is described elsewhere .…”

Selective Glucocorticoid Receptor Properties of GSK866 Analogs with Cysteine Reactive Warheads

“…Since the late 1990s, this has triggered researchers to synthetize various SEGRA and SEGRM compounds, with GSK866 and mapracorat being the prototypes of this non-steroidal class of compounds, in which bulky, bicyclic aromatic substituents account for the structural similarity to corticoids ( 7 , 13 – 15 , 18 – 20 ). In vivo efficacy for SEGRA/SEGRM compounds with reduced side effects has already been demonstrated for treatment of acute infections, such as rheumatoid arthritis, asthma, and colitis, in the clinic ( 20 – 22 ).…”