Cystic Fibrosis
Conditions
Keywords
inhaled dose, intravenous dose, healthy subjects, safety, tolerability, pharmacokinetics, AZD5634, jet nebulizer
Brief summary
This is a Phase 1, first-in-human (FIH) single ascending dose study being conducted to better understand the safety, tolerability and pharmacokinetics of AZD5634 in healthy subjects
Detailed description
This study is a Phase I, FIH, randomized, single-blinded (study center staff remain blinded during the dosing phase of the study), placebo-controlled, single ascending dose, sequential dose group study in healthy male subjects and/or female subjects of non-childbearing potential at a single study center to assess AZD5634 following inhaled and intravenous dose administration
Interventions
DRUGAZD5634 for inhalation
Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer
DRUGAZD5634 for infusion
Solution, citrate buffer, saline solution for infusion; strength 0.013 mg/mL
OTHERPlacebo
inactive substance
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated, written informed consent prior to any study specific procedures. 2. Healthy male and/or female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture. 3. Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: * Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range. * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation. 4. Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive. 5. Have a FEV1 (Forced expiratory volume in 1 second in liters) ≥ 80% of the predicted value at screening. 6. Provision of signed, written and dated informed consent for optional genetic/biomarker research.
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 administration of investigational medicinal product (IMP). 4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator. 5. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV). 6. Abnormal vital signs, after 10 minutes supine rest, at screening and check-in, defined as any of the following: * Systolic blood pressure (SBP) \< 90mmHg (millimeter of mercury) or ≥ 140 mmHg * Diastolic blood pressure (DBP) \< 50mmHg or ≥ 90 mmHg * Heart Rate \< 45 or \> 85 beats per minute (bpm) 7. Any clinically significant abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc (QT \[ECG interval measured from the onset of the QRS complex to the end of the T wave\] interval corrected for heart rate) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, at screening. 8. PR (PQ \[ECG interval measured from the onset of the P wave to the onset of the QRS complex\]) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation, at screening. 9. 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 (ECG interval measured from the onset of the QRS complex to the J point) \> 110 ms but \< 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation, at screening. 10. Serum/plasma potassium levels are outside the normal range and lower than 3.5 to 5.1 mEq/L (milliequivalents per liter) at screening and prior to dosing. 11. Has active lung disease/asthma that requires treatment. 12. Known or suspected history of drug abuse, as judged by the investigator. 13. Current smokers or those who have smoked or used nicotine products within the previous 3 months. 14. History of alcohol abuse or excessive intake of alcohol, as judged by the investigator. 15. Positive screen for drugs of abuse, cotinine (nicotine), or alcohol at screening or admission to the unit. 16. 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 AZD5634. 17. Excessive intake of caffeine containing drinks or food (e.g., coffee, tea, chocolate), as judged by the investigator. 18. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the administration of IMP. 19. 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 administration of IMP or longer if the medication has a long half-life. 20. Plasma donation within 1 month of screening or any blood donation/blood loss \> 500 mL during the 3 months prior to screening. 21. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the administration of IMP in this study. The period of exclusion is 3 months after the final dose from a previous study. Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. 22. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 23. Involvement of any Astra Zeneca, PAREXEL or study site employee or their close relatives. 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. Subjects who are vegans or have medical dietary restrictions. 26. Subjects who cannot communicate reliably with the investigator. In addition, any of the following is regarded as a criterion for exclusion from the genetic research: 27. Previous bone marrow transplant. 28. 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 AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose. | To assess the safety and tolerability of AZD5634 in terms of number of participants following inhaled administration of single-ascending doses (SAD) (Part A) and following administration of single inhaled and IV doses (Part B) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter AUC of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. AUC was estimated by AUC(0-last) + Clast/λz where Clast was the last observed quantifiable concentration. AUCs were calculated using the linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. AUC0-t is expanded as area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. Note:Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter AUC(0-t) of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the Absolute systemic bioavailability after inhalation (%), calculated separately as 100\*AUCinhalation\*Doseiv/(AUCiv\*Doseinhalation) |
| Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | -12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3) | To assess the pharmacokinetic parameter CLR of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter Cmax/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter t1/2λz of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter AUC0-t/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic (PK) parameter Cmax of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Systemic Clearance for AZD5634 Estimated as Dose Divided by AUC (Part B IV Dosing Only) (CL) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter CL of AZD5634 following single-dose IV administration of AZD5634 in Part B |
| Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter CL/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Mean Residence Time (MRT) - For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter MRT of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter MAT of AZD5634 following single-dose IV or inhalation administration of AZD5634 in Part B |
| Volume of Distribution for AZD5634 at Steady State (IV Administration), Estimated by Dividing the MRT by the Systemic CL (Part B IV Dosing Only) (Vss) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter Vss of AZD5634 following single-dose IV administration of AZD5634 in Part B |
| Volume of Distribution for AZD5634 at Terminal Phase (IV Administration), Estimated by Dividing the Systemic CL by λz (Part B IV Dosing Only) (Vz) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter Vz of AZD5634 following single-dose IV administration of AZD5634 in Part B |
| Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter Vz/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
| AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3) | To assess the pharmacokinetic parameter AUC/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics. |
Countries
United States
Participant flow
Recruitment details
Phase 1, first-in-human (FIH), single-blind, placebo-controlled, single ascending dose (SAD), sequential dose group study in healthy male participants and female participants of non-childbearing potential at 2 study centers (EPCU Baltimore and EPCU Los Angeles). The study comprised of Part A and Part B.
Pre-assignment details
The study consisted of a screening period (Days -28 to -1).
Participants by arm
| Arm | Count |
|---|---|
| AZD5634 - Inhaled 10 μg Participants received inhaled single doses of AZD5634 10 μg under fasted conditions | 6 |
| AZD5634 27 μg Participants received inhaled single doses of AZD5634 27 μg under fasted conditions | 7 |
| AZD5634 81 μg Participants received inhaled single doses of AZD5634 81 μg under fasted conditions | 6 |
| AZD5634 216 μg Participants received inhaled single doses of AZD5634 216 μg under fasted conditions | 6 |
| AZD5634 648 μg Participants received inhaled single doses of AZD5634 648 μg under fasted conditions | 6 |
| AZD5634 1296 μg Participants received inhaled single doses of AZD5634 1296 μg under fasted conditions | 6 |
| AZD5634 1692 μg Participants received inhaled single doses of AZD5634 1692 μg under fasted conditions | 6 |
| Placebo 2 participants per dose level received single dose of placebo in Part A | 14 |
| AZD5634 - IV 65 μg and IN 1692 μg After safety evaluation of all inhaled AZD5634 cohorts, 6 participants (who did not participate in Part A) were admitted for inhaled (1692 μg AZD5634) and IV (65 μg AZD5634) dosing (fixed dosing; IV first followed by inhalation), with at least a 14 day washout between dosing | 6 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Participant decision | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | AZD5634 - Inhaled 10 μg | AZD5634 27 μg | AZD5634 81 μg | AZD5634 216 μg | AZD5634 648 μg | AZD5634 1296 μg | AZD5634 1692 μg | Placebo | Total | AZD5634 - IV 65 μg and IN 1692 μg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part A | 36.5 Years STANDARD_DEVIATION 12.2 | 33.3 Years STANDARD_DEVIATION 9.3 | 31.8 Years STANDARD_DEVIATION 3.4 | 32.0 Years STANDARD_DEVIATION 6.9 | 37.7 Years STANDARD_DEVIATION 9.1 | 31.7 Years STANDARD_DEVIATION 5.2 | 35.2 Years STANDARD_DEVIATION 10.6 | 32.6 Years STANDARD_DEVIATION 8.9 | 34.0 Years STANDARD_DEVIATION 8.3 | — |
| Age, Continuous Part B | — | — | — | — | — | — | — | — | 32.0 Years STANDARD_DEVIATION 7.9 | 32.0 Years STANDARD_DEVIATION 7.9 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 5 Participants | 13 Participants | 60 Participants | 6 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 0 / 7 | 0 / 6 | 1 / 6 | 1 / 6 | 0 / 6 | 2 / 6 | 3 / 14 | 2 / 6 | 1 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 14 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B).
To assess the safety and tolerability of AZD5634 in terms of number of participants following inhaled administration of single-ascending doses (SAD) (Part A) and following administration of single inhaled and IV doses (Part B)
Time frame: Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose.
Population: All partcipants in safety analysis set who received at least 1 dose of IMP and for whom any safety post-dose data were available were included in the safety analysis for the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A - AZD5634 10 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 10 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 10 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 1 Participants |
| Part A - AZD5634 10 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 1 Participants |
| Part A - AZD5634 27 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 27 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 0 Participants |
| Part A - AZD5634 27 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 27 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 81 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 81 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 0 Participants |
| Part A - AZD5634 81 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 81 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 216 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 1 Participants |
| Part A - AZD5634 216 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 216 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 216 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 648 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 1 Participants |
| Part A - AZD5634 648 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 648 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 648 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 1296 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 0 Participants |
| Part A - AZD5634 1296 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 1296 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 1296 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - AZD5634 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part A - AZD5634 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 2 Participants |
| Part A - AZD5634 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - AZD5634 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - Placebo for AZD5634 | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part A - Placebo for AZD5634 | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part A - Placebo for AZD5634 | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 3 Participants |
| Part A - Placebo for AZD5634 | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part B - AZD5634 IV 65 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 2 Participants |
| Part B - AZD5634 IV 65 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
| Part B - AZD5634 IV 65 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part B - AZD5634 IV 65 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part B - AZD5634 IN 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during Follow-up | 0 Participants |
| Part B - AZD5634 IN 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE during treatment | 1 Participants |
| Part B - AZD5634 IN 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any AE with outcome = death | 0 Participants |
| Part B - AZD5634 IN 1692 µg | Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B). | Any SAE (including events with outcome = death) | 0 Participants |
Secondary
Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total)
To assess the Absolute systemic bioavailability after inhalation (%), calculated separately as 100\*AUCinhalation\*Doseiv/(AUCiv\*Doseinhalation)
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part B consisted of all participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated in each treatment period, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total) | NA Percentage of bioavailable dose | — |
| Part A - AZD5634 27 µg | Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total) | 2.928 Percentage of bioavailable dose | Geometric Coefficient of Variation 42.2 |
Secondary
Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F)
To assess the pharmacokinetic parameter CL/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | NA L/h | — |
| Part A - AZD5634 27 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | 1727 L/h | Standard Deviation 589.7 |
| Part A - AZD5634 81 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | 699.9 L/h | Standard Deviation 115.3 |
| Part A - AZD5634 216 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | 1518 L/h | Standard Deviation 852.7 |
| Part A - AZD5634 648 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | 929.8 L/h | Standard Deviation 548.2 |
| Part A - AZD5634 1296 µg | Apparent Clearance for AZD5634 Estimated as Dose Divided by AUC (Part A and Part B Inhaled Dosing Only) (CL/F) | 1346 L/h | Standard Deviation 457.8 |
Secondary
Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F)
To assess the pharmacokinetic parameter Vz/F of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | NA Litre | — |
| Part A - AZD5634 27 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | 3775 Litre | Standard Deviation 1306 |
| Part A - AZD5634 81 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | 1864 Litre | Standard Deviation 178.2 |
| Part A - AZD5634 216 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | 5416 Litre | Standard Deviation 1905 |
| Part A - AZD5634 648 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | 7115 Litre | Standard Deviation 2202 |
| Part A - AZD5634 1296 µg | Apparent Volume of Distribution for AZD5634 at Terminal Phase (Inhaled Administration), Estimated by Dividing the CL/F by λz (Part A and Part B Inhaled Dosing Only) (Vz/F) | 5361 Litre | Standard Deviation 1077 |
Secondary
Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B
To assess the pharmacokinetic parameter AUC of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. AUC was estimated by AUC(0-last) + Clast/λz where Clast was the last observed quantifiable concentration. AUCs were calculated using the linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. AUC0-t is expanded as area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. Note:Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | NA h*nmol/L | — |
| Part A - AZD5634 27 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 0.1757 h*nmol/L | Geometric Coefficient of Variation 34.9 |
| Part A - AZD5634 81 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 1.258 h*nmol/L | Geometric Coefficient of Variation 16.7 |
| Part A - AZD5634 216 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 1.299 h*nmol/L | Geometric Coefficient of Variation 57.2 |
| Part A - AZD5634 648 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 2.837 h*nmol/L | Geometric Coefficient of Variation 71.5 |
| Part A - AZD5634 1296 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 2.329 h*nmol/L | Geometric Coefficient of Variation 11.3 |
| Part A - AZD5634 1692 µg | Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B | 1.777 h*nmol/L | Geometric Coefficient of Variation 37.2 |
Comparison: Statistical Analysis for Part A95% CI: [0.905, 1.49]
Secondary
Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B
To assess the pharmacokinetic parameter AUC(0-t) of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 0.01920 h*nmol/L | Geometric Coefficient of Variation 60.1 |
| Part A - AZD5634 27 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 0.1120 h*nmol/L | Geometric Coefficient of Variation 62.2 |
| Part A - AZD5634 81 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 1.301 h*nmol/L | Geometric Coefficient of Variation 22 |
| Part A - AZD5634 216 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 1.244 h*nmol/L | Geometric Coefficient of Variation 57.2 |
| Part A - AZD5634 648 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 2.664 h*nmol/L | Geometric Coefficient of Variation 60.9 |
| Part A - AZD5634 1296 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 2.318 h*nmol/L | Geometric Coefficient of Variation 11.4 |
| Part A - AZD5634 1692 µg | Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B | 1.831 h*nmol/L | Geometric Coefficient of Variation 38 |
Comparison: Statistical Analysis for Part A95% CI: [1.34, 1.76]
Secondary
AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B
To assess the pharmacokinetic parameter AUC0-t/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 0.1762 h*nmol/L/umol | Geometric Coefficient of Variation 60.1 |
| Part A - AZD5634 27 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 0.3856 h*nmol/L/umol | Geometric Coefficient of Variation 62.2 |
| Part A - AZD5634 81 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 1.492 h*nmol/L/umol | Geometric Coefficient of Variation 22 |
| Part A - AZD5634 216 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 0.7137 h*nmol/L/umol | Geometric Coefficient of Variation 57.2 |
| Part A - AZD5634 648 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 1.170 h*nmol/L/umol | Geometric Coefficient of Variation 60.9 |
| Part A - AZD5634 1296 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 26.51 h*nmol/L/umol | Geometric Coefficient of Variation 11.4 |
| Part A - AZD5634 1692 µg | AUC0-t, Divided by the Dose Administered (AUC0-t/Dose) - For Part A and Part B | 0.8044 h*nmol/L/umol | Geometric Coefficient of Variation 38 |
Secondary
AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B
To assess the pharmacokinetic parameter AUC/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | NA h*nmol/L/umol | — |
| Part A - AZD5634 27 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 0.6046 h*nmol/L/umol | Geometric Coefficient of Variation 34.9 |
| Part A - AZD5634 81 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 1.444 h*nmol/L/umol | Geometric Coefficient of Variation 16.7 |
| Part A - AZD5634 216 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 0.7450 h*nmol/L/umol | Geometric Coefficient of Variation 57.2 |
| Part A - AZD5634 648 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 1.246 h*nmol/L/umol | Geometric Coefficient of Variation 71.5 |
| Part A - AZD5634 1296 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 26.63 h*nmol/L/umol | Geometric Coefficient of Variation 11.3 |
| Part A - AZD5634 1692 µg | AUC, Divided by the Dose Administered (AUC/Dose) - For Part A and Part B | 0.7805 h*nmol/L/umol | Geometric Coefficient of Variation 37.2 |
Secondary
Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B
To assess the pharmacokinetic parameter Cmax/Dose of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.1473 nmol/L/umol | Geometric Coefficient of Variation 18.8 |
| Part A - AZD5634 27 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.1576 nmol/L/umol | Geometric Coefficient of Variation 45.2 |
| Part A - AZD5634 81 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.3415 nmol/L/umol | Geometric Coefficient of Variation 20 |
| Part A - AZD5634 216 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.1745 nmol/L/umol | Geometric Coefficient of Variation 46.5 |
| Part A - AZD5634 648 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.2335 nmol/L/umol | Geometric Coefficient of Variation 51.6 |
| Part A - AZD5634 1296 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 69.41 nmol/L/umol | Geometric Coefficient of Variation 8.9 |
| Part A - AZD5634 1692 µg | Cmax, Divided by the Dose Aministered (Cmax/Dose) - For Part A and Part B | 0.1673 nmol/L/umol | Geometric Coefficient of Variation 34.7 |
Secondary
Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT)
To assess the pharmacokinetic parameter MAT of AZD5634 following single-dose IV or inhalation administration of AZD5634 in Part B
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part B consisted of all participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated in each treatment period, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT) | NA hour | — |
| Part A - AZD5634 27 µg | Mean Absorption Time, Calculated as MRTinhaled - MRTIV (Part B Only) (MAT) | 4.236 hour | Standard Deviation 1.302 |
Secondary
Mean Residence Time (MRT) - For Part A and Part B
To assess the pharmacokinetic parameter MRT of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Mean Residence Time (MRT) - For Part A and Part B | NA hour | — |
| Part A - AZD5634 27 µg | Mean Residence Time (MRT) - For Part A and Part B | 2.742 hour | Standard Deviation 0.1741 |
| Part A - AZD5634 81 µg | Mean Residence Time (MRT) - For Part A and Part B | 3.529 hour | Standard Deviation 0.5093 |
| Part A - AZD5634 216 µg | Mean Residence Time (MRT) - For Part A and Part B | 4.157 hour | Standard Deviation 1.166 |
| Part A - AZD5634 648 µg | Mean Residence Time (MRT) - For Part A and Part B | 6.000 hour | Standard Deviation 2.009 |
| Part A - AZD5634 1296 µg | Mean Residence Time (MRT) - For Part A and Part B | 0.1928 hour | Standard Deviation 0.02455 |
| Part A - AZD5634 1692 µg | Mean Residence Time (MRT) - For Part A and Part B | 4.428 hour | Standard Deviation 1.293 |
Secondary
Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B
To assess the pharmacokinetic (PK) parameter Cmax of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.01605 nmol/L | Geometric Coefficient of Variation 18.8 |
| Part A - AZD5634 27 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.04581 nmol/L | Geometric Coefficient of Variation 45.2 |
| Part A - AZD5634 81 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.2977 nmol/L | Geometric Coefficient of Variation 20 |
| Part A - AZD5634 216 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.3043 nmol/L | Geometric Coefficient of Variation 46.5 |
| Part A - AZD5634 648 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.5316 nmol/L | Geometric Coefficient of Variation 51.6 |
| Part A - AZD5634 1296 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 6.070 nmol/L | Geometric Coefficient of Variation 8.9 |
| Part A - AZD5634 1692 µg | Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B | 0.3808 nmol/L | Geometric Coefficient of Variation 34.7 |
Comparison: Statistical Analysis for Part A95% CI: [0.396, 0.853]
Secondary
Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B
To assess the pharmacokinetic parameter CLR of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: -12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 1.449 L/h | Standard Deviation 0.1332 |
| Part A - AZD5634 27 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.8099 L/h | Standard Deviation 0.2849 |
| Part A - AZD5634 81 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.5828 L/h | Standard Deviation 0.1724 |
| Part A - AZD5634 216 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.9063 L/h | Standard Deviation 0.2459 |
| Part A - AZD5634 648 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.7333 L/h | Standard Deviation 0.1893 |
| Part A - AZD5634 1296 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.6247 L/h | Standard Deviation 0.3373 |
| Part A - AZD5634 1692 µg | Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B | 0.6939 L/h | Standard Deviation 0.1044 |
Secondary
Systemic Clearance for AZD5634 Estimated as Dose Divided by AUC (Part B IV Dosing Only) (CL)
To assess the pharmacokinetic parameter CL of AZD5634 following single-dose IV administration of AZD5634 in Part B
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part B consisted of all participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated in each treatment period, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Systemic Clearance for AZD5634 Estimated as Dose Divided by AUC (Part B IV Dosing Only) (CL) | 37.74 L/h | Standard Deviation 4.22 |
Secondary
Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B
To assess the pharmacokinetic parameter t1/2λz of AZD5634 following single-dose inhalation administration of AZD5634 in Part A and following single-dose IV or inhalation administration of AZD5634 in Part B. Note: Due to the participant and/or data exclusion described above, there are no PK data available for the 10 μg dose cohort and very limited data for the 27 μg dose cohort. Therefore, these 2 cohorts were not included in PK results interpretation and summary statistics.
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part A consisted of participants in the safety analysis set who received AZD5634 and for Part B consisted of participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | NA Hours | — |
| Part A - AZD5634 27 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 1.519 Hours | Standard Deviation 0.1499 |
| Part A - AZD5634 81 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 1.903 Hours | Standard Deviation 0.4722 |
| Part A - AZD5634 216 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 3.144 Hours | Standard Deviation 2.25 |
| Part A - AZD5634 648 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 7.552 Hours | Standard Deviation 5.438 |
| Part A - AZD5634 1296 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 0.1923 Hours | Standard Deviation 0.05567 |
| Part A - AZD5634 1692 µg | Terminal Half-life (t1/2λz), Estimated as (ln2)/λz - For Part A and Part B | 3.184 Hours | Standard Deviation 1.816 |
Secondary
Volume of Distribution for AZD5634 at Steady State (IV Administration), Estimated by Dividing the MRT by the Systemic CL (Part B IV Dosing Only) (Vss)
To assess the pharmacokinetic parameter Vss of AZD5634 following single-dose IV administration of AZD5634 in Part B
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part B consisted of all participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated in each treatment period, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Volume of Distribution for AZD5634 at Steady State (IV Administration), Estimated by Dividing the MRT by the Systemic CL (Part B IV Dosing Only) (Vss) | 7.202 Litre | Standard Deviation 0.3915 |
Secondary
Volume of Distribution for AZD5634 at Terminal Phase (IV Administration), Estimated by Dividing the Systemic CL by λz (Part B IV Dosing Only) (Vz)
To assess the pharmacokinetic parameter Vz of AZD5634 following single-dose IV administration of AZD5634 in Part B
Time frame: At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)
Population: The PK analysis set for Part B consisted of all participants who completed both treatment periods and for whom at least one of the PK parameters Cmax, AUC0-t or AUC were calculated in each treatment period, with no major protocol deviations thought to impact on the analysis of the PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A - AZD5634 10 µg | Volume of Distribution for AZD5634 at Terminal Phase (IV Administration), Estimated by Dividing the Systemic CL by λz (Part B IV Dosing Only) (Vz) | 10.25 Litre | Standard Deviation 1.804 |