Asthma, Chronic Obstructive Pulmonary Disease COPD
Conditions
Keywords
Safety, Pharmacokinetics, Pharmacodynamics, Glucocorticoid receptor modulator, Healthy male subjects
Brief summary
This is a randomized, single-blind, placebo-controlled, sequential-group study to assess the safety and tolerability as well as how the drug (AZD7594) affects the body (pharmacodynamics \[PD\]) and how the body affects the drug (pharmacokinetics \[PK\]) when AZD7594 is given as single and multiple ascending doses once daily by inhalation to healthy male Japanese subjects, compared with placebo (non-active drug)
Detailed description
This is a phase I, randomized, single-blind, placebo controlled, sequential-group design study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD7594 after single and multiple ascending doses given once daily by inhalation in healthy male Japanese subjects, compared with placebo
Interventions
DRUGAZD7594 inhalation powder (200 μg)
200 μg AZD7594 inhalation powder via multi-dose dry powder inhaler (DPI)
DRUGAZD7594 inhalation powder (400 μg)
Cohort 2: 400 μg AZD7594 inhalation powder via multi-dose DPI Cohort 3: 1600 μg (4 x 400 μg inhalations) AZD7594 inhalation powder via multi-dose DPI
DRUGAZD7594 pressurized inhalation suspension (200 μg)
400 μg (2 x 200 μg inhalations) AZD7594 pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)
DRUGAZD7594 placebo inhalation powder
AZD7594 placebo inhalation powder via multi-dose DPI
DRUGAZD7594 placebo pressurized inhalation suspension
AZD7594 placebo pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male Japanese subjects aged 20 to 45 years with suitable veins for cannulation or repeated venipuncture. A Japanese male subject is defined as being born in Japan, having both parents and four grandparents who are Japanese. The subject must not have lived outside of Japan for more than 5 years. 3. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 45 kg and no more than 100 kg inclusive. 4. Provision of signed, written and dated informed consent for optional genetic research Note: If a subject declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the subject. The subject will not be excluded from other aspects of the study described in this protocol.
Exclusion criteria
1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. 2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. 3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational drug administration. 4. Any contraindication against the use of vagolytic or sympaticomimetic drugs, as judged by the investigator. 5. Any clinically significant abnormalities in clinical chemistry, hematology, urinalysis, physical examination, vital signs, electrocardiogram (ECG) or lung function results at baseline, as judged by the investigator. 6. Known Gilbert's syndrome, family history of Gilbert's syndrome or suspicion of Gilbert's syndrome based on liver function tests. 7. Use of systemic glucocorticosteroids within 6 weeks of enrollment. 8. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV). 9. Known or suspected hypersensitivity to investigational product or excipients. 10. Plasma donation within one month of screening or any blood donation/blood loss \> 500 mL during the 3 months prior to screening. 11. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following: * Systolic blood pressure (BP) \< 90mmHg or \> 140 mmHg * Diastolic BP \< 60mmHg or \> 90 mmHg * Pulse rate \< 40 or \> 85 beats per minute (bpm) 12. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy. 13. Prolonged QT interval corrected for heart rate (HR) using Fridericia's formula (QTcF) \> 450 ms or family history of long QT syndrome. 14. PR(PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation). 15. PR (PQ) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree AV block, or AV dissociation. 16. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS \> 110 ms but \< 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation. 17. Known or suspected history of drug abuse, as judged by the investigator. 18. Current smokers or those who have smoked or used nicotine products within the previous 3 months. 19. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator. 20. Positive screen for drugs of abuse or cotinine (nicotine) at screening or admission to the unit. 21. History of severe allergy/hypersensitivity or ongoing clinically significant allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to ADZ7594. 22. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator. 23. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of investigational drug. 24. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of investigational drug or longer if the medication has a long half-life. 25. Has received another new chemical entity (defined as a compound which has not been approved for marketing in the US) within 30 days or at least 5 half-lives (whichever is longer) of the first administration of investigational drug in this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest. Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. 26. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 27. Subjects who have previously received AZD7594. 28. Involvement of any Astra Zeneca or study site employee or their close relatives. 29. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements. 30. Subjects who are vegans or have medical dietary restrictions. 31. Subjects who cannot communicate reliably with the investigator. It is acceptable to make use of an interpreter. The informed consent document (ICD) must be available in the Japanese language. In addition, any of the following is regarded as a criterion for exclusion from the genetic research: 32. Previous bone marrow transplant. 33. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | At screening (Day -28, Day -02 and Day -1), Treatment period (Days 1 to 20) and Follow-up (Day 29). | To assess the safety and tolerability of single and multiple doses of AZD7594 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. tmax was defined as time to reach maximum plasma concentration, taken directly from the individual concentration-time curve. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC [0-last]) | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. AUC (0-last) was defined as the area under the plasma concentration-time curve from time zero to the time of last quantifiable analyte concentration. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero to 24 Hours After Dosing (AUC [0-24]). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. AUC (0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. AUC was defined as area under the plasma concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUC(0-last) + Clast/λz where Clast is the last observed quantifiable concentration. NOTE: No results were available for participants belonging to AZD7594 2ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Terminal Elimination Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve(Lamda z or λz). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Half-life Associated With the Terminal Slope of a Semi-logarithmic Concentration-time Curve (t1/2λz). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. NOTE: No results were available for participants belonging to AZD7594 400ug group. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Mean Residence Time From Time Zero Extrapolated to Infinity (MRT). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. MRT was defined as Mean residence time from time zero extrapolated to infinity. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (AZD7594) (CL/F). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. CL/F was defined as apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594). NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration, Estimated by Dividing CL/F by Lamda z (Vz/F) | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Vz/F was defined as apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing the apparent clearance (CL/F) by λz. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. Cmax/D was defined as observed maximum plasma concentration divided by the dose administered. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D). | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. AUC/D was defined as Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D) | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Days 5 to 15: Pre-dose | Cmin was defined as observed minimum plasma concentration, taken directly from the individual concentration-time curve |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max). | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. Css,max was defined as observed maximum plasma concentration at steady state, taken directly from the individual concentration-time curve. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Cmin, ss was defined as observed minimum concentration, taken directly from the individual concentration-time curve. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Cav was defined as average concentration over one dosing interval. |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax) | Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Cmax was defined as observed maximum plasma concentration, taken directly from the individual concentration-time curve. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. AUC(0-last) was defined as Area under the plasma concentration-time curve from time zero to the time of the last quantifiable analyte concentration. |
| Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D). | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Css,max/D was defined as observed maximum plasma concentration divided by the dose administered. |
| Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D. | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as the area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered. |
| Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least. |
| Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz. | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose | Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. Participant count analyzed = 1 |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation). | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Peak trough fluctuation calculated as \[100\*(Css,max- Css,min)/Cav\]. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Accumulation Ratio Calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Accumulation ratio calculated as AUC(0-24) on Day 16/AUC(0-24) on Day 1. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP) | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. Temporal change parameter, calculated as AUC(0-24) \[Day 16\]/AUC \[Day 1\]. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | Day 1 predose spot-collection and interval collection up to 96 hours postdose | Assessment of the urine PK following a single dose of AZD7594. Ae (t1-t2) was defined as the amount of AZD7594 excreted into the urine from time t1 to t2. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | Day 1 predose spot-collection and interval collection up to 96 hours postdose | Assessment of the urine PK following a single dose of AZD7594. Ae(0-last) was defined as Cumulative amount of AZD7594 excreted from time zero to the last sampling interval. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | Day 1 predose spot-collection and interval collection up to 96 hours postdose | Assessment of the urine PK following a single dose of AZD7594. fe(0-last)% was defined as Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose. |
| Rate and Extent of Absorption of AZD7594 by Assessment of the Renal Clearance, Estimated by Dividing Ae(0-96) by AUC(0-96) (CLR) | Day 1 predose spot-collection and interval collection up to 96 hours postdose | Assessment of the urine PK following a single dose of AZD7594. CLR was defined as the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96). |
| Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day -1 (- 24 hours predose) up to 24 hours postdose; Day 1 and Day 16 | Assessment of the plasma pharmacodynamics (PD) effects of AZD7594 after single and multiple ascending inhaled doses. AUEC(0-24) was defined as area under the effect curve for plasma cortisol from time zero to 24 hours after dosing. |
| Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Day 1 (predose) and Day 16 (24 hours postdose) | Assessment of the plasma PD following a single dose of AZD7594 |
| Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 1 (predose) and Day 16 (24 hours postdose) | Assessment of the plasma PD following a single dose of AZD7594 |
| Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max). | Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. | Assessment of the plasma PK following a single dose of AZD7594. tss,max was defined as Time to reach maximum concentration, taken directly from the individual concentration-time curve. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at PAREXEL Early Phase Clinical Unit - Los Angeles
Pre-assignment details
Twenty-seven participants were randomized in 3 sequential cohorts. Each cohort consisted of nine participants in it. Within each cohort, 7 participants were randomly assigned to receive AZD7594 (different doses) and 2 subjects were randomly assigned to receive placebo.
Participants by arm
| Arm | Count |
|---|---|
| AZD7594 200 μg Participants received 200 μg inhaled AZD7594 via multi-dose dry powder inhaler (DPI) (1 x 200 μg inhalation) | 7 |
| AZD7594 400 μg Participants received 400 μg inhaled AZD7594 via multi-dose DPI (1 x 400 μg inhalation) | 7 |
| AZD7594 1600 μg Participants received 1600 μg inhaled AZD7594 via multi-dose DPI (4 x 400 μg inhalations). | 7 |
| Palcebo Participants received placebo | 6 |
| Total | 27 |
Baseline characteristics
| Characteristic | AZD7594 200 μg | AZD7594 400 μg | AZD7594 1600 μg | Palcebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 32.7 Years STANDARD_DEVIATION 5.41 | 34.1 Years STANDARD_DEVIATION 6.41 | 33.6 Years STANDARD_DEVIATION 6.43 | 35.7 Years STANDARD_DEVIATION 5.54 | 34.0 Years STANDARD_DEVIATION 5.73 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 7 Participants | 6 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 7 | 1 / 7 | 1 / 7 | 1 / 6 | 5 / 21 | 6 / 27 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 7 | 0 / 6 | 0 / 21 | 0 / 27 |
Outcome results
Primary
Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events
To assess the safety and tolerability of single and multiple doses of AZD7594
Time frame: At screening (Day -28, Day -02 and Day -1), Treatment period (Days 1 to 20) and Follow-up (Day 29).
Population: All subjects who received at least one dose of IMP and for whom any post-dose data were available were included in the safety analysis set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD7594 200 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| AZD7594 200 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| AZD7594 200 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
| AZD7594 200 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 3 Pariticpants |
| AZD7594 400 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| AZD7594 400 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| AZD7594 400 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
| AZD7594 400 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 1 Pariticpants |
| AZD7594 1600 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| AZD7594 1600 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| AZD7594 1600 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
| AZD7594 1600 μg | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 1 Pariticpants |
| Total AZD7594 | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
| Total AZD7594 | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 5 Pariticpants |
| Total AZD7594 | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| Total AZD7594 | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| Placebo | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| Placebo | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| Placebo | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
| Placebo | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 1 Pariticpants |
| All Subjects | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE leading to discontinuation of IP | 0 Pariticpants |
| All Subjects | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE | 6 Pariticpants |
| All Subjects | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any AE with outcome = death | 0 Pariticpants |
| All Subjects | Safety and Tolerability of AZD7594 by Assessment of the Number of Participants With Adverse Events | Any SAE including events with outcome =death | 0 Pariticpants |
Secondary
Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS)
Assessment of the plasma PD following a single dose of AZD7594
Time frame: Day 1 (predose) and Day 16 (24 hours postdose)
Population: The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 1 / pre-dose | 6.716 μmol/L | Standard Deviation 1.405 |
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 17 / 24 h | 6.104 μmol/L | Standard Deviation 0.862 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 17 / 24 h | 6.250 μmol/L | Standard Deviation 1.005 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 1 / pre-dose | 7.380 μmol/L | Standard Deviation 2.429 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 1 / pre-dose | 6.747 μmol/L | Standard Deviation 2.936 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 17 / 24 h | 7.125 μmol/L | Standard Deviation 2.708 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 1 / pre-dose | 6.280 μmol/L | Standard Deviation 1.829 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Dehydroepiandrosterone Sulphate (DHEAS) | Result: Day 17 / 24 h | 6.392 μmol/L | Standard Deviation 2.179 |
Secondary
Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin
Assessment of the plasma PD following a single dose of AZD7594
Time frame: Day 1 (predose) and Day 16 (24 hours postdose)
Population: The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 17 / 24 h | 17.81 μg/L | Standard Deviation 8.55 |
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 1 / pre-dose | 21.31 μg/L | Standard Deviation 17.22 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 17 / 24 h | 19.66 μg/L | Standard Deviation 11.56 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 1 / pre-dose | 23.13 μg/L | Standard Deviation 10.02 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 17 / 24 h | 13.37 μg/L | Standard Deviation 8.26 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 1 / pre-dose | 20.01 μg/L | Standard Deviation 5.77 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 1 / pre-dose | 22.92 μg/L | Standard Deviation 20.13 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of Plasma Concentration of Osteocalcin | Day 17 / 24 h | 17.03 μg/L | Standard Deviation 5.6 |
Secondary
Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]).
Assessment of the plasma pharmacodynamics (PD) effects of AZD7594 after single and multiple ascending inhaled doses. AUEC(0-24) was defined as area under the effect curve for plasma cortisol from time zero to 24 hours after dosing.
Time frame: Day -1 (- 24 hours predose) up to 24 hours postdose; Day 1 and Day 16
Population: The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day -1 | 294273.817 min*nmol/L | Standard Deviation 66921.717 |
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 16 | 253767.846 min*nmol/L | Standard Deviation 11407.064 |
| AZD7594 200 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 1 | 268228.553 min*nmol/L | Standard Deviation 34086.352 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day -1 | 286677.610 min*nmol/L | Standard Deviation 41429.744 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 16 | 249097.459 min*nmol/L | Standard Deviation 46925.914 |
| AZD7594 400 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 1 | 274458.997 min*nmol/L | Standard Deviation 36894.669 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 1 | 264104.101 min*nmol/L | Standard Deviation 47619.269 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day -1 | 298827.031 min*nmol/L | Standard Deviation 57082.835 |
| AZD7594 1600 μg | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 16 | 213505.523 min*nmol/L | Standard Deviation 40857.201 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day -1 | 275402.666 min*nmol/L | Standard Deviation 42811.506 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 16 | 273268.869 min*nmol/L | Standard Deviation 57797.995 |
| Total AZD7594 | Pharmacodynamic Analysis of AZD7594 by Assessment of the Area Under the Effect Curve for Plasma Cortisol From Time Zero to 24 Hours After Dosing (AUEC [0-24]). | Day 1 | 256226.560 min*nmol/L | Standard Deviation 48755.915 |
95% CI: [86.88, 122.09]ANCOVA
95% CI: [77.32, 109.04]ANCOVA
95% CI: [89.4, 125.49]ANCOVA
95% CI: [75.35, 106.16]ANCOVA
95% CI: [84.12, 118.46]ANCOVA
95% CI: [63.4, 89.61]ANCOVA
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D.
Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as the area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D. | 7351 (pmol*h/L)/umol | Geometric Coefficient of Variation 13.4 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D. | 6691 (pmol*h/L)/umol | Geometric Coefficient of Variation 33.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment AUC(0-24)/D. | 7889 (pmol*h/L)/umol | Geometric Coefficient of Variation 13.2 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24)
Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24) | 2426 pmol*h/L | Geometric Coefficient of Variation 13.4 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24) | 4409 pmol*h/L | Geometric Coefficient of Variation 33.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of AUC(0-24) | 20830 pmol*h/L | Geometric Coefficient of Variation 13.2 |
90% CI: [0.951, 1.14]Linear Model
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz)
Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz) | 0.013393 l/hour | Geometric Coefficient of Variation 19.8 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz) | 0.011465 l/hour | Geometric Coefficient of Variation 38.8 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of Lamda z (λz) | 0.010660 l/hour | Geometric Coefficient of Variation 27.4 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz.
Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. Participant count analyzed = 1
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz. | NA Hours |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz. | NA Hours |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of t1/2λz. | NA Hours |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Accumulation Ratio Calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC).
Assessment of the plasma PK following a single dose of AZD7594. Accumulation ratio calculated as AUC(0-24) on Day 16/AUC(0-24) on Day 1.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Accumulation Ratio Calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). | 3.562 Ratio | Geometric Coefficient of Variation 15.7 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Accumulation Ratio Calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). | 4.067 Ratio | Geometric Coefficient of Variation 43.7 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Accumulation Ratio Calculated as AUC(0-24) on Day 16/AUC (0-24) on Day 1 (RAC). | 3.437 Ratio | Geometric Coefficient of Variation 7.3 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2])
Assessment of the urine PK following a single dose of AZD7594. Ae (t1-t2) was defined as the amount of AZD7594 excreted into the urine from time t1 to t2.
Time frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 0-6h | 1.856 pmol | Standard Deviation 4.91 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 6-12h | 1.434 pmol | Standard Deviation 3.795 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 12-24h | 1.893 pmol | Standard Deviation 5.008 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 24-48h | NA pmol | — |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 48-72h | NA pmol | — |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 72-96h | NA pmol | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 72-96h | NA pmol | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 0-6h | 6.738 pmol | Standard Deviation 9.751 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 24-48h | NA pmol | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 48-72h | NA pmol | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 6-12h | 5.031 pmol | Standard Deviation 6.645 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 12-24h | 1.907 pmol | Standard Deviation 5.046 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 6-12h | 73.15 pmol | Standard Deviation 53.23 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 12-24h | 73.13 pmol | Standard Deviation 50.96 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 72-96h | 48.95 pmol | Standard Deviation 48.49 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 24-48h | 107.9 pmol | Standard Deviation 76.97 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 0-6h | 55.64 pmol | Standard Deviation 58.01 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Amount of AZD7594 Excreted Into the Urine From Time t1 to t2 (Ae [t1-t2]) | 48-72h | 72.43 pmol | Standard Deviation 58.77 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (AZD7594) (CL/F).
Assessment of the plasma PK following a single dose of AZD7594. CL/F was defined as apparent total body clearance after extravascular administration estimated as dose divided by AUC (AZD7594). NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (AZD7594) (CL/F). | NA L/h | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (AZD7594) (CL/F). | NA L/h | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (AZD7594) (CL/F). | 144.5 L/h | Geometric Coefficient of Variation 22.9 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration, Estimated by Dividing CL/F by Lamda z (Vz/F)
Assessment of the plasma PK following a single dose of AZD7594. Vz/F was defined as apparent volume of distribution during the terminal phase after extravascular administration, estimated by dividing the apparent clearance (CL/F) by λz. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration, Estimated by Dividing CL/F by Lamda z (Vz/F) | NA Litres | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration, Estimated by Dividing CL/F by Lamda z (Vz/F) | NA Litres | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration, Estimated by Dividing CL/F by Lamda z (Vz/F) | 9297 Litres | Geometric Coefficient of Variation 24.1 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D)
Assessment of the plasma PK following a single dose of AZD7594. AUC(0-24)/D was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing divided by the dose administered.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D) | 2064 (pmol*h/L)/umol | Geometric Coefficient of Variation 11.5 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D) | 1645 (pmol*h/L)/umol | Geometric Coefficient of Variation 19.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-24) Divided by the Dose Administered (AUC(0-24)/D) | 2295 (pmol*h/L)/umol | Geometric Coefficient of Variation 18.4 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last)
Assessment of the plasma PK following a single dose of AZD7594. AUC(0-last) was defined as Area under the plasma concentration-time curve from time zero to the time of the last quantifiable analyte concentration.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last) | 6136 pmol*h/L | Geometric Coefficient of Variation 16.2 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last) | 11490 pmol*h/L | Geometric Coefficient of Variation 36.9 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC(0-last) | 54120 pmol*h/L | Geometric Coefficient of Variation 11.5 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D).
Assessment of the plasma PK following a single dose of AZD7594. AUC/D was defined as Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D). | NA (pmol*h/L)/umol | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D). | NA (pmol*h/L)/umol | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the AUC Divided by the Dose Administered (AUC/D). | 6918 (pmol*h/L)/umol | Geometric Coefficient of Variation 22.9 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D).
Assessment of the plasma PK following a single dose of AZD7594. Cmax/D was defined as observed maximum plasma concentration divided by the dose administered.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D). | 169.9 (pmol/L)/umol | Geometric Coefficient of Variation 22 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D). | 116.7 (pmol/L)/umol | Geometric Coefficient of Variation 34.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cmax Divided by the Dose Administered (Cmax/D). | 163.2 (pmol/L)/umol | Geometric Coefficient of Variation 22.4 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D).
Assessment of the plasma PK following a single dose of AZD7594. Css,max/D was defined as observed maximum plasma concentration divided by the dose administered.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D). | 498.0 (pmol/L)/umol | Geometric Coefficient of Variation 14 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D). | 396.4 (pmol/L)/umol | Geometric Coefficient of Variation 37 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Css,Max Divided by the Dose Administered (Css,Max/D). | 456.9 (pmol/L)/umol | Geometric Coefficient of Variation 14.7 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last])
Assessment of the urine PK following a single dose of AZD7594. Ae(0-last) was defined as Cumulative amount of AZD7594 excreted from time zero to the last sampling interval.
Time frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-6h | 1.856 pmol | Standard Deviation 4.91 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-12h | 3.290 pmol | Standard Deviation 8.705 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-24h | 5.183 pmol | Standard Deviation 13.71 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-48h | 5.183 pmol | Standard Deviation 13.71 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-72h | 5.183 pmol | Standard Deviation 13.71 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-96h | 5.183 pmol | Standard Deviation 13.71 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-96h | 13.68 pmol | Standard Deviation 17.07 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-6h | 6.738 pmol | Standard Deviation 9.751 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-48h | 13.68 pmol | Standard Deviation 17.07 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-72h | 13.68 pmol | Standard Deviation 17.07 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-12h | 11.77 pmol | Standard Deviation 15.25 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-24h | 13.68 pmol | Standard Deviation 17.07 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-12h | 128.8 pmol | Standard Deviation 83.03 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-24h | 201.9 pmol | Standard Deviation 117.9 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-96h | 431.2 pmol | Standard Deviation 262.2 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-48h | 309.9 pmol | Standard Deviation 175.6 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-6h | 55.64 pmol | Standard Deviation 58.01 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Cumulative Amount of AZD7594 Excreted From Time Zero to the Last Sampling Interval (Ae [0-last]) | 0-72h | 382.3 pmol | Standard Deviation 219.7 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin)
Cmin was defined as observed minimum plasma concentration, taken directly from the individual concentration-time curve
Time frame: Days 5 to 15: Pre-dose
Population: The pharmacokinetic (PK) analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - 1 hour | 139.5 pmol/L | Geometric Coefficient of Variation 8.216 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - 1 hour | 106.4 pmol/L | Geometric Coefficient of Variation 19.69 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 6 - Pre-dose | 29.35 pmol/L | Geometric Coefficient of Variation 17.83 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - Pre-dose | 78.39 pmol/L | Geometric Coefficient of Variation 9.019 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 9 - Pre-dose | 60.37 pmol/L | Geometric Coefficient of Variation 16.48 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - 1 hour | 59.81 pmol/L | Geometric Coefficient of Variation 27.6 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 11 - Pre-dose | 68.39 pmol/L | Geometric Coefficient of Variation 19.83 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 10 - Pre-dose | 61.88 pmol/L | Geometric Coefficient of Variation 21.52 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 13 - Pre-dose | 79.31 pmol/L | Geometric Coefficient of Variation 12.92 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 7 - Pre-dose | 41.59 pmol/L | Geometric Coefficient of Variation 10.33 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 15 - Pre-dose | 82.40 pmol/L | Geometric Coefficient of Variation 13.3 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - Pre-dose | NA pmol/L | — |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - Pre-dose | 51.99 pmol/L | Geometric Coefficient of Variation 12.29 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 14 - Pre-dose | 77.04 pmol/L | Geometric Coefficient of Variation 7.165 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - 1 hour | 219.8 pmol/L | Geometric Coefficient of Variation 26.21 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - Pre-dose | 16.27 pmol/L | Geometric Coefficient of Variation 13.13 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - 1 hour | 77.10 pmol/L | Geometric Coefficient of Variation 26.92 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 6 - Pre-dose | 47.75 pmol/L | Geometric Coefficient of Variation 20.76 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 7 - Pre-dose | 76.91 pmol/L | Geometric Coefficient of Variation 16.27 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - Pre-dose | 92.18 pmol/L | Geometric Coefficient of Variation 18.17 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - 1 hour | 162.3 pmol/L | Geometric Coefficient of Variation 20.93 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 9 - Pre-dose | 108.2 pmol/L | Geometric Coefficient of Variation 25.11 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 10 - Pre-dose | 119.3 pmol/L | Geometric Coefficient of Variation 31.01 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 11 - Pre-dose | 136.3 pmol/L | Geometric Coefficient of Variation 26.2 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - Pre-dose | 142.6 pmol/L | Geometric Coefficient of Variation 30.88 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 13 - Pre-dose | 145.5 pmol/L | Geometric Coefficient of Variation 38.15 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 14 - Pre-dose | 147.0 pmol/L | Geometric Coefficient of Variation 34.87 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 15 - Pre-dose | 151.9 pmol/L | Geometric Coefficient of Variation 35.42 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 14 - Pre-dose | 718.4 pmol/L | Geometric Coefficient of Variation 23.65 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - Pre-dose | 603.8 pmol/L | Geometric Coefficient of Variation 16.84 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - Pre-dose | 458.4 pmol/L | Geometric Coefficient of Variation 22.39 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 7 - Pre-dose | 369.0 pmol/L | Geometric Coefficient of Variation 20.88 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 12 - 1 hour | 925.8 pmol/L | Geometric Coefficient of Variation 16.61 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 6 - Pre-dose | 252.2 pmol/L | Geometric Coefficient of Variation 24.53 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - Pre-dose | 68.91 pmol/L | Geometric Coefficient of Variation 21.55 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 13 - Pre-dose | 698.3 pmol/L | Geometric Coefficient of Variation 19.89 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 5 - 1 hour | 404.2 pmol/L | Geometric Coefficient of Variation 22.74 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 10 - Pre-dose | 554.2 pmol/L | Geometric Coefficient of Variation 23.65 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 9 - Pre-dose | 548.3 pmol/L | Geometric Coefficient of Variation 25.72 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 15 - Pre-dose | 694.9 pmol/L | Geometric Coefficient of Variation 11.67 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 11 - Pre-dose | 623.5 pmol/L | Geometric Coefficient of Variation 21.1 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Observed Minimum Plasma Concentration (Cmin) | Day 8 - 1 hour | 793.0 pmol/L | Geometric Coefficient of Variation 26.6 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation).
Assessment of the plasma PK following a single dose of AZD7594. Peak trough fluctuation calculated as \[100\*(Css,max- Css,min)/Cav\].
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The pharmacodynamics analysis set will include all subjects who receive at least 1 dose of IMP and for whom it is possible to calculate the cortisol AUEC on Day -1, Day 1 and/or Day 16 and with no major protocol deviations considered to impact on the analysis of the PD (cortisol, plasma DHEAS and osteocalcin) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation). | 80.12 Percentage of fluctuation | Geometric Coefficient of Variation 23.8 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation). | 64.61 Percentage of fluctuation | Geometric Coefficient of Variation 21.8 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Peak Trough Fluctuation (%Fluctuation). | 68.08 Percentage of fluctuation | Geometric Coefficient of Variation 21 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%)
Assessment of the urine PK following a single dose of AZD7594. fe(0-last)% was defined as Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an AZD7594, estimated by dividing Ae(0-last) by dose.
Time frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 0-6h | 0.0005623 Percentage of dose excreted unchanged | Standard Deviation 0.001488 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 6-12h | 0.0004346 Percentage of dose excreted unchanged | Standard Deviation 0.00115 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 12-24h | 0.0005736 Percentage of dose excreted unchanged | Standard Deviation 0.001518 |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 24-48h | NA Percentage of dose excreted unchanged | — |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 48-72h | NA Percentage of dose excreted unchanged | — |
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 72-96h | NA Percentage of dose excreted unchanged | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 72-96h | NA Percentage of dose excreted unchanged | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 0-6h | 0.001022 Percentage of dose excreted unchanged | Standard Deviation 0.00148 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 24-48h | NA Percentage of dose excreted unchanged | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 48-72h | NA Percentage of dose excreted unchanged | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 6-12h | 0.0007634 Percentage of dose excreted unchanged | Standard Deviation 0.001008 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 12-24h | 0.0002894 Percentage of dose excreted unchanged | Standard Deviation 0.0007657 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 6-12h | 0.002771 Percentage of dose excreted unchanged | Standard Deviation 0.002016 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 12-24h | 0.002770 Percentage of dose excreted unchanged | Standard Deviation 0.00193 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 72-96h | 0.001854 Percentage of dose excreted unchanged | Standard Deviation 0.001837 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 24-48h | 0.004088 Percentage of dose excreted unchanged | Standard Deviation 0.002915 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 0-6h | 0.002108 Percentage of dose excreted unchanged | Standard Deviation 0.002197 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Percentage of Dose Excreted Unchanged Into the Urine From Time Zero to the Last Measured Time Point for an AZD7594, Estimated by Dividing Ae(0-last) by Dose (fe(0-last)%) | 48-72h | 0.002743 Percentage of dose excreted unchanged | Standard Deviation 0.002226 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Renal Clearance, Estimated by Dividing Ae(0-96) by AUC(0-96) (CLR)
Assessment of the urine PK following a single dose of AZD7594. CLR was defined as the renal clearance, estimated by dividing Ae(0-96) by AUC(0-96).
Time frame: Day 1 predose spot-collection and interval collection up to 96 hours postdose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Renal Clearance, Estimated by Dividing Ae(0-96) by AUC(0-96) (CLR) | NA L/h | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Renal Clearance, Estimated by Dividing Ae(0-96) by AUC(0-96) (CLR) | NA L/h | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Renal Clearance, Estimated by Dividing Ae(0-96) by AUC(0-96) (CLR) | 0.02329 L/h | Geometric Coefficient of Variation 98.8 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP)
Assessment of the plasma PK following a single dose of AZD7594. Temporal change parameter, calculated as AUC(0-24) \[Day 16\]/AUC \[Day 1\]. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP) | NA Ratio | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP) | NA Ratio | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Temporal Change Parameter (TCP) | 1.147 Ratio | Geometric Coefficient of Variation 7.7 |
Secondary
Rate and Extent of Absorption of AZD7594 by Assessment of the Terminal Elimination Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve(Lamda z or λz).
Assessment of the plasma PK following a single dose of AZD7594. λz was defined as terminal elimination rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Terminal Elimination Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve(Lamda z or λz). | 0.015573 l/h | Geometric Coefficient of Variation 24.5 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Terminal Elimination Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve(Lamda z or λz). | 0.011058 l/h | Geometric Coefficient of Variation 18.3 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 by Assessment of the Terminal Elimination Rate Constant, Estimated by Log-linear Least Squares Regression of the Terminal Part of the Concentration-time Curve(Lamda z or λz). | 0.013862 l/h | Geometric Coefficient of Variation 21.4 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC [0-last])
Assessment of the plasma PK following a single dose of AZD7594. AUC (0-last) was defined as the area under the plasma concentration-time curve from time zero to the time of last quantifiable analyte concentration.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC [0-last]) | 1314 h*pmol/L | Geometric Coefficient of Variation 28.2 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC [0-last]) | 2736 h*pmol/L | Geometric Coefficient of Variation 12.2 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUC [0-last]) | 13960 h*pmol/L | Geometric Coefficient of Variation 18.2 |
90% CI: [1.06, 1.23]Linear Model
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC).
Assessment of the plasma PK following a single dose of AZD7594. AUC was defined as area under the plasma concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUC(0-last) + Clast/λz where Clast is the last observed quantifiable concentration. NOTE: No results were available for participants belonging to AZD7594 2ug and AZD7594 400ug groups.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC). | NA h*pmol/L | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC). | NA h*pmol/L | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero Extrapolated to Infinity (AUC). | 18260 h*pmol/L | Geometric Coefficient of Variation 22.9 |
90% CI: [0.801, 1.31]Linear Model
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero to 24 Hours After Dosing (AUC [0-24]).
Assessment of the plasma PK following a single dose of AZD7594. AUC (0-24) was defined as area under the plasma concentration-time curve from time zero to 24 hours after dosing.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero to 24 Hours After Dosing (AUC [0-24]). | 681.1 h*pmol/L | Geometric Coefficient of Variation 11.5 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero to 24 Hours After Dosing (AUC [0-24]). | 1084 h*pmol/L | Geometric Coefficient of Variation 19.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the AUC From Time Zero to 24 Hours After Dosing (AUC [0-24]). | 6060 h*pmol/L | Geometric Coefficient of Variation 18.4 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav)
Assessment of the plasma PK following a single dose of AZD7594. Cav was defined as average concentration over one dosing interval.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav) | 101.1 pmol/L | Geometric Coefficient of Variation 13.4 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav) | 183.7 pmol/L | Geometric Coefficient of Variation 33.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Average Concentration Over One Dosing Interval (Cav) | 867.8 pmol/L | Geometric Coefficient of Variation 13.2 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max).
Assessment of the plasma PK following a single dose of AZD7594. Css,max was defined as observed maximum plasma concentration at steady state, taken directly from the individual concentration-time curve.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max). | 164.3 pmol/L | Geometric Coefficient of Variation 14 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max). | 261.2 pmol/L | Geometric Coefficient of Variation 37 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmax at Steady State (Css,Max). | 1206 pmol/L | Geometric Coefficient of Variation 14.7 |
90% CI: [0.87, 1.09]Linear Model
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss)
Assessment of the plasma PK following a single dose of AZD7594. Cmin, ss was defined as observed minimum concentration, taken directly from the individual concentration-time curve.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss) | 82.15 pmol/L | Geometric Coefficient of Variation 12.8 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss) | 140.6 pmol/L | Geometric Coefficient of Variation 38.5 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Cmin at Steady State (Cmin, ss) | 600.0 pmol/L | Geometric Coefficient of Variation 27 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Half-life Associated With the Terminal Slope of a Semi-logarithmic Concentration-time Curve (t1/2λz).
Assessment of the plasma PK following a single dose of AZD7594. t1/2λz was defined as half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve. NOTE: No results were available for participants belonging to AZD7594 400ug group.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Half-life Associated With the Terminal Slope of a Semi-logarithmic Concentration-time Curve (t1/2λz). | 39.88 Hours | Standard Deviation 5.441 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Half-life Associated With the Terminal Slope of a Semi-logarithmic Concentration-time Curve (t1/2λz). | NA Hours | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Half-life Associated With the Terminal Slope of a Semi-logarithmic Concentration-time Curve (t1/2λz). | 43.57 Hours | Standard Deviation 3.815 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Mean Residence Time From Time Zero Extrapolated to Infinity (MRT).
Assessment of the plasma PK following a single dose of AZD7594. MRT was defined as Mean residence time from time zero extrapolated to infinity. NOTE: No results were available for participants belonging to AZD7594 200ug and AZD7594 400ug groups.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Mean Residence Time From Time Zero Extrapolated to Infinity (MRT). | NA Hours | — |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Mean Residence Time From Time Zero Extrapolated to Infinity (MRT). | NA Hours | — |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Mean Residence Time From Time Zero Extrapolated to Infinity (MRT). | 65.03 Hours | Geometric Coefficient of Variation 4.7 |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax)
Assessment of the plasma PK following a single dose of AZD7594. Cmax was defined as observed maximum plasma concentration, taken directly from the individual concentration-time curve.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The pharmacokinetic (PK) analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax) | 56.05 pmol/L | Geometric Coefficient of Variation 22 |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax) | 76.93 pmol/L | Geometric Coefficient of Variation 34.4 |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Observed Maximum Plasma Concentration (Cmax) | 430.8 pmol/L | Geometric Coefficient of Variation 22.4 |
90% CI: [0.882, 1.15]Linear Model
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax)
Assessment of the plasma PK following a single dose of AZD7594. tmax was defined as time to reach maximum plasma concentration, taken directly from the individual concentration-time curve.
Time frame: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 0.25 Hours |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 0.52 Hours |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Time to Reach Maximum Plasma Concentration (Tmax) | 0.50 Hours |
Secondary
Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max).
Assessment of the plasma PK following a single dose of AZD7594. tss,max was defined as Time to reach maximum concentration, taken directly from the individual concentration-time curve.
Time frame: Day 16: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post-dose.
Population: The PK analysis set consisted of all subjects in the safety analysis set who received AZD7594 and had at least 1 measured AZD7594 plasma concentration at a scheduled PK time point post-dose, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD7594 200 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max). | 0.25 Hours |
| AZD7594 400 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max). | 1.50 Hours |
| AZD7594 1600 μg | Rate and Extent of Absorption of AZD7594 (Inhalation/ Administration Via DPI) by Assessment of the Tmax at Steady State (Tss,Max). | 1.50 Hours |