A Study to Assess the Bioavailability and to Compare the Pharmacokinetics of AZD7594 Inhaled Via Monodose Inhaler and Multiple-dose Dry Powder Inhalers (DPI) or Pressurized Metered-dose Inhaler (pMDI) in Healthy Male Subjects

Chronic Obstructive Pulmonary Disease (COPD) Clinical Trial

Official title:

An Open Label, Partially Randomized, Four-period Study in Healthy Male Subjects to Investigate the Bioavailability and Pharmacokinetics of a Single Dose of AZD7594 When Administered Intravenously, Orally and Inhaled Via Two Different Dry Powder Inhalers (DPI) and a Pressurized Metered-dose Inhaler (pMDI)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02648438
• Other study ID #: D3741C00004
• Status: Completed
• Phase: Phase 1
• First received: December 26, 2015
• Last updated: June 20, 2016
• Start date: January 2016
• Est. completion date: June 2016

Study information

• Verified date: June 2016
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is an open-label,partially randomized, four-period study in healthy male subjects to assess the bioavailability and pharmacokinetics of a single dose of AZD7594 when administered intravenously, orally and inhaled via two different dry powder inhalers (DPIs) and a pressurized meter-dose inhaler (pMDI)

Description:

This study is an open-label, partially randomized, 4-period, 5-treatment study in healthy male subjects, performed at a single study center. All subjects will receive the 4 of the 5 treatments. The IV infusion will be fixed as the first treatment (Period 1), the Monodose inhaler will be fixed as the second treatment (Period 2) and the oral formulation will be fixed as the fourth treatment (Period 4). During Period 3, subjects are split into 2 equal cohorts, multiple-dose DPI and pMDI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures.

2. Healthy male subjects aged 18 - 45 years with suitable veins for cannulation or repeated venipuncture.

3. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg.

4. Subjects should be willing to follow reproductive restrictions to prevent pregnancy and drug exposure of a female partner and refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of investigational product.

5. Be able to inhale from the dry powder inhaler (DPI) devices and the pressurized metered-dose inhaler (pMDI) device according to given instructions.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer'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, major medical/surgical procedure, or trauma within 4 weeks of the first administration of Investigational medicinal product (IMP).

4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results at screening and check-in, as judged by the investigator.

5. Any clinically significant abnormal findings in vital signs after a 5 minute rest at screening and check-in, as judged by the investigator, defined as any of the following:

• Systolic blood pressure (BP) > 140 mm Hg;

• Systolic BP < 90 mm Hg;

• Diastolic BP > 90 mm Hg;

• Diastolic BP < 60 mm Hg; or

• Heart rate < 40 or > 85 beats per minute (bpm).

6. Any clinically significant abnormities in physical examination or lung function, as judged by the investigator.

7. Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) at screening and check-in, as judged by the investigator.

8. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc (QT interval corrected) interval changes. This includes subjects with any of the following:

• Clinically significant PR (PQ) (ECG interval measured from the onset of the P wave to the onset of the QRS complex) interval prolongation;

• Intermittent or persistent second or third degree AV block;

• Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS (ECG interval measured from the onset of the QRS complex to the J point) > 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; or

• Abnormal T wave morphology, particularly in the protocol defined primary lead.

9. Prolonged QTcF (QT interval corrected for heart rate using Fridericia's formula) > 450 msec or family history of long QT (ECG interval measured from the onset of the QRS complex to the end of the T wave) syndrome.

10. Known or suspected history of drug abuse, as judged by the investigator

11. Current smokers or those who have smoked or used nicotine products within the previous 3 months.

12. History of alcohol abuse or excessive intake of alcohol as judged by the investigator.

13. Positive screen for drugs of abuse, alcohol, and cotinine at screening or on each admission to the study center.

14. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594 or to excipients.

15. Excessive intake of caffeine containing drinks e.g., coffee, tea, caffeine containing energy drinks and cola (in total no more than 3 cups per day).

16. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.

17. Use of any prescribed or non-prescribed medication including vaccines, antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life. Occasional use of paracetamol/acetaminophen is allowed for minor pains and headaches (no more than 3000 mg/day).

18. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening.

19. Has participated in a clinical study investigating clinical evaluation methods 1 month (or at least 5 half-lives) prior to the administration of investigational product.

20. Known Gilbert's syndrome, family history of Gilbert's syndrome or suspicion of Gilbert's syndrome based on liver function tests.

21. Any contraindication against the use of vagolytic or sympaticomimetic drugs, as judged by the investigator.

22. Involvement of any AstraZeneca, PAREXEL or study site employee or their close relatives.

23. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody.

24. 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.

25. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Asthma,
• Chronic Obstructive Pulmonary Disease (COPD)
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• AZD7594 Solution for infusion (150 µg intravenous formulation)
Solution for infusion 0.01 mg/ml; AZD7594 150 µg IV
• AZD7594 Oral suspension (1200 µg oral formulation)
0.1 - 10 mg/g oral solution; AZD7594 1200 µg oral
• AZD7594 Inhalation powder (400 µg) by DPI Device 1 (monodose inhaler)
Inhalation powder, hard capsules 400 µg Monodose inhaler; AZD7594 400 µg by dry powder inhaler (DPI) Device 1 (Monodose inhaler)
• AZD7594 Inhalation powder (400 µg) by DPI device 2 (multiple-dose inhaler)
Inhalation powder, multiple-dose dry powder inhaler (DPI) 400 µg; AZD7594 400 µg by DPI Device 2 (multiple-dose DPI)
• AZD7594 Pressurized inhalation suspension (400 µg) by pMDI
Inhalation suspension 200 µg; AZD7594 400 µg by pressurized metered-dose inhaler (pMDI); 2 puffs x 200 µg = 400 µg

Locations

Country	Name	City	State
United States	Research Site	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetics of AZD7594 delivered by Monodose inhaler and multiple-dose DPI or pMDI in terms of pulmonary bioavailability after inhalation (Fpulmonary)		Predose, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours postdose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the absolute systemic bioavailability after oral administration (Fpo)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the absolute systemic bioavailability after inhalation (Finhalation, total)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12,16, 24, 36, 48 , 72 and 96 hours	No
Secondary	Safety profile of AZD7594 by assessment of the number of adverse events		From screening until the follow-up phone call, up to 10 weeks	Yes
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the observed maximum plasma concentration(Cmax)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the time to reach maximum plasma concentration (tmax)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (?z)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the terminal half-life (t½?z), estimated as (ln2)/ ?z		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the area under plasma concentration-time curve from time zero extrapolated to infinity (AUC)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the mean absorption time (MAT)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the mean residence time (MRT)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the systemic clearance for parent drug estimated as dose divided by AUC (CL)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the volume of distribution at terminal phase (Vz)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following i.v administration by assessment of the volume of distribution for parent drug at steady state (Vss)		Blood samples taken pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 4, 6, 8, 12,16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the observed maximum plasma concentration (Cmax)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the time to reach maximum plasma concentration (tmax)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (?z)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the terminal half-life (t½?z), estimated as (ln2)/ ?z		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the area under plasma concentration-time curve from time zero extrapolated to infinity (AUC)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the mean absorption time (MAT)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the mean residence time (MRT)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the apparent total body clearance after extravascular administration (CL/F)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following oral administration by assessment of the apparent volume of distribution for parent drug at terminal phase (Vz/F)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the observed maximum plasma concentration (Cmax)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the time to reach maximum plasma concentration (tmax)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the area under the plasma concentration-curve from time zero to time of last quantifiable concentration (AUC0-t)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (?z)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the terminal half-life (t½?z), estimated as (ln2)/ ?z		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the area under plasma concentration-time curve from time zero extrapolated to infinity (AUC)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the mean absorption time (MAT)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the mean residence time (MRT)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the apparent total body clearance after extravascular administration (CL/F)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the apparent volume of distribution for parent drug at terminal phase (Vz/F)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12, 16, 24, 36, 48, 72 and 96 hours post dose	No
Secondary	Pharmacokinetics of AZD7594 following inhalation by DPI1, DPI2 and pMDI inhaler by assessment of the oral bioavailability after inhaled treatment (Foral)		Blood samples taken pre-dose and at 15, 30 and 45 minutes and 1, 2, 4, 6, 8, 12,16, 24, 36, 48 , 72 and 96 hours post dose	No
Secondary	Safety profile of AZD7594 by assessment of physical examinations		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of physical examinations		On Day -1	Yes
Secondary	Safety profile of AZD7594 by assessment of physical examinations		On Day 5	Yes
Secondary	Safety profile of AZD7594 by assessment of 12-lead electrocardiograms (ECGs)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of 12-lead electrocardiograms (ECGs)		On Day 1 pre-dose until 5 hours 55 minutes post-dose	Yes
Secondary	Safety profile of AZD7594 by assessment of cardiac telemetry		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of cardiac telemetry		On Day 1 pre-dose until 6 hours post-dose	Yes
Secondary	Safety profile of AZD7594 by assessment of vital signs (blood pressure)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of vital signs (pulse rate)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of vital signs (oral temperature)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of vital signs (blood pressure)		On Day 1 pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 12.0 and 24.0 hours post-dose	Yes
Secondary	Safety profile of AZD7594 by assessment of vital signs (oral temperature)		On Day 1 pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 12.0 and 24.0 hours post-dose	Yes
Secondary	Safety profile of AZD7594 by assessment of spirometry		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of spirometry		On Day 1 pre-dose and 30 and 60 minutes post-dose in Period 2 and Period 3 (maximum 14 days apart)	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (hematology)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (clinical chemistry)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (urinalysis)		At screening	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (hematology)		On Day -1	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (clinical chemistry)		On Day -1	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (urinalysis)		On Day -1	Yes
Secondary	Safety profile of AZD7594 by assessment of taste (10 point rating scale for sweet, salty, sour, bitter, hot/spicy, metallic and overall taste)		On Day 1 post-dose in period 2 and Period 3 (maximum 14 days apart)	Yes
Secondary	Safety profile of AZD7594 by assessment of taste (fish taste, yes or no)		On Day 1 post-dose in Period 2 and Period 3 (maximum 14 days apart)	Yes
Secondary	Safety profile of AZD7594 by assessment of taste (does the medicine smell, yes or no)		On Day 1 post-dose in Period 2 and Period 3 (maximum 14 days apart)	Yes
Secondary	Safety profile of AZD7594 by assessment of taste (10 point rating scale for smell and the willingness to take the medicine again)		On Day 1 post-dose in Period 2 and Period 3 (maximum 14 days apart)	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (hematology)		On Day 5	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (clinical chemistry)		On Day 5	Yes
Secondary	Safety profile of AZD7594 by assessment of clinical laboratory assessments (urinalysis)		On Day 5	Yes