AZD7594 is a non steroidal, potent and selective modulator of the glucocorticoid receptor (GR) under development for once daily inhaled treatment of chronic obstructive pulmonary disease (COPD) and asthma. Abediterol is a novel and selective β2 adrenergic receptor agonist with the potential for once daily treatment of asthma and COPD in fixed dose combination (FDC) with an ICS or a novel anti inflammatory (AI) agent. This study will be the first clinical study for the combination exposure of AZD7594 with abediterol as 2 compounds in FDC or in free combination via 2 separate dry powder inhalers (DPIs). This study will be conducted in healthy male subjects to minimize the effects of concomitant disease states or medications on study measurements.
AZD7594 is a non steroidal, potent and selective modulator of the glucocorticoid receptor (GR) under development for once daily inhaled treatment of chronic obstructive pulmonary disease (COPD) and asthma. Inhaled corticosteroids (ICS) have not been definitively shown to decrease the rate of decline in lung function that is typical of COPD. The aim is to develop AZD7594 as a well tolerated once daily selective inhaled GR modulator with an acceptable side effect profile compared to conventional ICS on the market. Abediterol is a novel and selective β2 adrenergic receptor agonist with the potential for once daily treatment of asthma and COPD in fixed dose combination (FDC) with an ICS or a novel anti inflammatory (AI) agent Fixed dose ICS/LABA combination treatment is more effective in improving lung function, health status and reducing exacerbations than the individual components. The long term goal of abediterol development program in COPD is to investigate it both as a monotherapy and as a combination therapy in conjunction with an ICS or a novel anti inflammatory agent. This study will be the first clinical study for the combination exposure of AZD7594 with abediterol as 2 compounds in FDC or in free combination via 2 separate dry powder inhalers (DPIs). This study will be conducted in healthy male subjects to minimize the effects of concomitant disease states or medications on study measurements. Subjects will receive all 4 treatments in a randomized order. Given that the treatment in each period is a single dose of AZD7594, a 21 (±2) day wash out should be adequate to prevent carry over effect to next period. The abediterol elimination half life is shorter than that of AZD7594. Therefore, a 21 (±2) day wash out is sufficient for the elimination of both AZD7594 and abediterol. Overall, pre-clinical and clinical data generated to date with abediterol show expected safety profile, and support the continued studies with abediterol.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Treatment A: Abediterol 2.5 μg via DPI
Treatment B: AZD7594 440 μg via DPI
Treatment C: AZD7594/abediterol 440 μg/2.5 μg FDC via DPI
Treatment D: AZD7594 440 μg and abediterol 2.5 μg free combination administered via 2 separate DPIs
Research Site
Berlin, Germany
Area under the plasma concentration time curve (AUC) of abediterol and AZD7594 from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Maximum observed plasma concentration (AUClast), taken directly from the individual concentration time curve of abediterol and AZD7594.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Observed maximum concentration (Cmax) of abediterol and AZD7594, taken directly from the individual concentration time curve.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t½λz) of abediterol and AZD7594 using plasma concentrations, estimated as (ln2)/λz.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Time to reach maximum observed plasma concentration (tmax) of abediterol and AZD7594 using plasma concentrations, taken directly from the individual concentration time curve.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Mean residence time (MRT) of abediterol and AZD7594.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Apparent estimated as dose divided by AUC.total body clearance of drug from plasma after extravascular administration (CL/F) of abediterol and AZD7594,
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
The time interval (h) of the log linear regression to determine t1/2λz (λz upper and λz lower) of abediterol and AZD7594.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Terminal elimination rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz, N) of abediterol and AZD7594.
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Regression coefficient adjusted for λz, N observations, goodness of fit statistic for calculation of λz (Rsq_adj) of abediterol and AZD7594
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Percentage of AUC obtained by extrapolating the area under the plasma concentration time curve from the time of the last quantifiable concentration to infinity (%AUCextr) of abediterol and AZD7594
Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs
Time frame: Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements
Safety and tolerability of single inhaled doses of AZD7594 and abediterol alone and in combination assessed by recording the AEs, physical examination, electrocardiogram readings, vital signs, spirometry and clinical laboratory assessments.
Safety and tolerability of single inhaled doses of AZD7594 and abediterol alone and in combination in healthy male subjects will be assessed by recording the AEs, physical examination, electrocardiogram (12-lead paper print-out ECG \[pECG\], digital ECG \[dECG\] and telemetry), vital signs (pulse rate, BP and oral body temperature), spirometry and clinical laboratory assessments (hematology, clinical chemistry including serum potassium and glucose and urinalysis).
Time frame: From Screening (maximum of 28 days) till Follow up visit (10 to 14 days post final dose), an average of 24 weeks
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.