A Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD7594 Inhaled Formulation in Healthy Japanese Men

AstraZeneca27 enrolled

Overview

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)

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Conditions

Asthma Chronic Obstructive Pulmonary Disease COPD

Interventions

AZD7594 inhalation powder (200 μg)DRUG

200 μg AZD7594 inhalation powder via multi-dose dry powder inhaler (DPI)

AZD7594 inhalation powder (400 μg)DRUG

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

AZD7594 pressurized inhalation suspension (200 μg)DRUG

400 μg (2 x 200 μg inhalations) AZD7594 pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)

Eligibility

Sex: MALEMin age: 20 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Research Site

Glendale, California, United States

Outcomes

Primary Outcomes

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).

Secondary Outcomes

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.

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.

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

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]).

Data from ClinicalTrials.gov

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AZD7594 placebo inhalation powder via multi-dose DPI

AZD7594 placebo pressurized inhalation suspensionDRUG

AZD7594 placebo pressurized inhalation suspension via pressurized metered dose inhaler (pMDI)

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

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

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

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

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

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.

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.

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

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.

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.

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

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

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.