Mass Balance Recovery, Pharmacokinetics and Metabolite Profile and Identification of [14C]AZD7594

Study Overview
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Brief Summary
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AZD7594 is in clinical development for the treatment of asthma. This is a single centre, open-label, single period study in 6 healthy subjects, to determine the mass balance recovery and generate samples to enable metabolite profiling and structural identification of AZD7594. Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing not more than (NMT) 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The IV dose will be administered approximately 10 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8).

Detailed Description
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This is a single centre, open-label, single period study in 6 healthy male and non-pregnant, non-lactating female subjects to determine the mass balance recovery after a single intravenous (IV) dose of [14C]AZD7594 and to generate samples to enable metabolite profiling and structural identification of AZD7594 in plasma, urine and faeces. It is planned to enrol 6 subjects to ensure data in at least 4 evaluable subjects. A subject will be considered evaluable if they have provided mass balance and PK samples for up to 48 h after drug administration. Subjects will be screened for eligibility to participate in the study up to 28 days before dosing. Eligible subjects will be admitted to the clinical unit in the afternoon on the day before dosing (Day 1). Subjects will be dosed on the morning of Day 1 in the fasted state (8 h overnight fast). Before oral inhalation of AZD7594 using the Dry Powder Inhaler (DPI), all subjects must demonstrate their ability to use the DPI as intended. Subjects will receive training with an empty DPI at screening, Day -1 and pre-dose (optional) in accordance with study specific instructions. Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The infusion of the IV dose will be started approximately 15 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8). Whole blood, plasma, urine and faeces will be collected from pre-dose until discharge (168 h post-dose; Day 8). Any accidental sources of elimination (eg emesis) will be collected and sent to the mass balance laboratory for total radioactivity analysis.

Official Title
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A Phase I, Open-Label Study to Assess Mass Balance Recovery, Pharmacokinetics, Metabolite Profile & Metabolite Identification After Intravenous Microdose Administration of [14C]AZD7594 & Inhaled Administration of AZD7594 in Healthy Subjects

Conditions
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Asthma

Intervention / Treatment
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* Drug: Intravenous Infusion
* Drug: Inhaled dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated, written informed consent prior to any study specific procedures. Healthy male or non-pregnant, non-lactating female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture. Have a body mass index of 18.5 to 35.0 kg/m2, and weigh at least 50 kg and no more than 100 kg, as measured at screening. Must have regular bowel movements (ie, average stool production of ≥1 and ≤3 stools per day). Must be willing and able to communicate and participate in the whole study. Must agree to adhere to the contraception requirements defined in Section 9.4 of the protocol. Must demonstrate the ability to use the study inhalation device properly. Exclusion Criteria: 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 of the volunteer's ability to participate in the study. History or presence of clinically significant gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP. Subjects with Gilbert's syndrome or subjects with a history of cholecystectomy or gall stones. Subjects with pregnant partners Any confirmed clinically significant abnormalities in clinical chemistry, haematology or urinalysis as judged by the investigator. Any confirmed clinically significant abnormal findings in vital signs or 12-lead ECG as judged by the investigator. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results. Has received any other new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose. Note: subjects consented and screened, but not randomised in this study or a previous Phase I study are not excluded. Plasma donation within 1 month of screening or any blood donation/loss of more than 500 mL of blood during the 3 months prior to screening. 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 the formulation excipients including lactose. Hay fever is allowed unless it is active. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months. Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative urine pregnancy test and screening and admission). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle stimulating hormone [FSH] concentration ≥40 IU/L). Confirmed positive screen for drugs of abuse at screening or admission to the clinical unit or positive screen for alcohol at screening or admission to the clinical unit. Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Subjects should stop using these herbal medications 14 days prior to administration of AZD7594. Use of any prescribed or nonprescribed medication including antacids, H2 antagonists, PPI, analgesics (other than paracetamol/acetaminophen up to 4 g/day), vitamins and minerals during the 14 days prior to administration of AZD7594 or longer if the medication has a longer half-life (see Section 11.4 of the protocol). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor. Known or suspected history of alcohol or drug abuse within the past 2 years or regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) Subjects who are study site employees, or immediate family members of a study site or sponsor employee Subjects who have previously been enrolled in this study. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study. Subjects who have been enrolled in an ADME study in the last 12 months Judgment by the investigator that the volunteer should not participate in the study if they have any ongoing or recent (ie during the screening period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with the study procedures, restrictions and requirements. History of infantile bronchiolitis, a history of asthma, adverse reaction or allergy to the inhaled medication or any excipients Upper respiratory tract infection (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within the last 3 months Subjects who are unable to demonstrate their ability to fulfil the physical demands of the study Failure to satisfy the investigator of fitness to participate for any other reason.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Only one study arm<br>[14C]AZD7594 Solution for Infusion 5 µg/mL (1.1 kBq/mL) AZD7594 Inhalation Powder, SD3FL Inhaler | Drug: Intravenous Infusion<br>* 30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 hour infusion.<br>Drug: Inhaled dose<br>* A single inhalation on one occasion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AZD7594 excreted (Ae) | Assessment of total radioactivity by measuring AZD7594 excreted (Ae) | Urine and faecal samples collected from pre-dose until 168 hours post-dose | 
| AZD7594 excreted and expressed as a percentage of the administered dose (Fe) | Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (Fe) | Urine and faecal samples colected from pre-dose until 168 hours post-dose | 
| Cumulative amount of AZD7594 excreted (CumAe) | Assessment of total radioactivity by measuring the cumulative amount of AZD7594 excreted (CumAe) | Urine and faecal samples collected from pre-dose until 168 hours post-dose | 
| Cumulative amount of AZD7594 excreted and expressed as a percentage of the administered dose (CumFe) | Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (CumFe) | Urine and faecal samples collected from pre-dose until 168 hours post-dose | 
| Assessment of metabolites in plasma by liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of metabolites in faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Collection of faecal samples from pre-dose until 168 hours post-dose | 
| Assessment of metabolites in urine by liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Assessment of metabolites and structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Collection of urine samples from pre-dose until 168 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of routes and rates of elimination of [14C]AZD7594 | Assessment of total radioactivity by measuring AZD7594 excreted (Ae), cumulative recovery (Cumae), Ae as a percentage of the administered dose (Fe) and cumulative recovery expressed as a percentage of the dose (CumFe) | Collection of urine and faecal samples from pre-dose until 168 hours post-dose | 
| Determination of the chemical structure of the major metabolites of [14C]AZD7594 | Structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry | Collection of urine adn faeces samples from pre-dose until 168 hours post-dose | 
| Evaluation of whole blood:plasma concentration ratios for total radioactivity | Assessment of total radioactivity by measuring AZD7594 in blood and plasma | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | Time from dosing at which Cmax was apparent (tmax) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The maximum observed plasma concentration (Cmax) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The area under the concentration-time curve from dosing to the last measurable concentration (AUClast) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The percentage of AUC extrapolated beyond the last measured time point (AUC%extr) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | The apparent terminal elimination half-life (t½) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | Total clearance (CL) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | Volume of distribution (Vz) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | Volume of distribution at steady state (Vss) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the IV PK of [14C]AZD7594 and total radioactivity | Mean residence time (MRT) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The time from dosing at which Cmax was apparent (tmax) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The maximum observed plasma concentration (Cmax) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The area under the concentration-time curve from dosing to the last measurable concentration (AUClast) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The percentage of AUC extrapolated beyond the last measured time point(AUC%exre) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | The apparent terminal elimination half-life (t½) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | Apparent total clearance (CL/F) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | Apparent volume of distribution (Vz/F) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Assessment of the inhaled PK of AZD7594 | Absolute bioavailability (F) | Collection of plasma samples from pre-dose until 168 hours post-dose | 
| Number of adverse events (AE) | Safety and tolerability assessed through incidence of AE | AEs recorded from the time of informed consent until discharge from the study (168 hours post-dose) |