An ADME Study of [14C]AZD4604 and the Absolute Bioavailability of AZD4604

NCT06157255 | Completed Phase 1

• 1 other identifier: D8210C00004
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The Sponsor is developing the test medicine, AZD4604, as a potential treatment for asthma. Asthma is a common lung condition caused by inflammation (swelling) of the breathing tubes that carry air in and out of the lungs, causing occasional breathing difficulties such as wheezing, shortness of breath, chest tightness and cough. This study in healthy volunteers will explore the following questions.

• Does the test medicine cause any important side effects?
• What are the blood levels of the test medicine and how quickly does the body get rid of it?
• How much of the test medicine gets into the bloodstream?
• How does the body break down and get rid of the test medicine? This study will take place at one non-NHS site in Nottingham, and plans to enrol 8 healthy men and women aged 18-65 years who will be involved in both parts of the study.

Conditions

Asthma

Keywords

Asthma

Outcome Measures

Primary Outcomes (31)

• Amount of AZD4604 excreted (Ae) - Part 1

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Amount of AZD4604 excreted expressed as a fraction of dose excreted (Fe) - Part 1

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• The cumulative amount of AZD4604 excreted (CumAe) - Part 1

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Cumulative amount of AZD4604 excreted expressed as a fraction of dose excreted (CumFe) - Part 1

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Time to maximum concentration (tmax) for AZD4604 and total radioactivity - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time 0 extrapolated to infinity for AZD4604 and total radioactivity (AUC-inf) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Maximum observed concentration (Cmax) for AZD4604 and total radioactivity - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time 0 to the time of the last measurable concentration for AZD4604 and total radioactivity (AUC0-t) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time of the last measurable concentration to infinity as a percentage of the area under the curve extrapolated to infinity (AUCextrap) and total radioactivity - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Terminal elimination half-life of AZD4604 (t1/2) and total radioactivity - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• First order rate constant associated with the terminal (log-linear) portion of the curve for AZD4604 (λz) and total radioactivity - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Total body clearance calculated after a single IV administration (CL) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Total body clearance calculated after a single extravascular administration where F (fraction of dose bioavailable) is unknown (CL/F) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single IV administration (Vz) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single extravascular administration where F (fraction of dose bioavailable) is unknown (Vz/F) - Part 1

  PK of AZD4604 and \[14C\]AZD4604 in plasma

  Plasma sample collection from pre-dose to 336 hours post-dose

• Assessment of metabolites in plasma, urine and faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry - Part 1

  Metabolite profiling and structural identification from plasma, urine and faecal samples

  Plasma, urine and faces sample collection from pre-dose to 336 hours post-dose

• Amount of AZD4604 excreted (Ae) - Part 2

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Amount of AZD4604 excreted expressed as a fraction of dose excreted (Fe) - Part 2

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• The cumulative amount of AZD4604 excreted (CumAe) - Part 2

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Cumulative amount of AZD4604 excreted expressed as a fraction of dose excreted (CumFe) - Part 2

  Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Time to maximum concentration (tmax) for AZD4604 and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time 0 extrapolated to infinity for AZD4604 and total radioactivity (AUC-inf) - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Maximum observed concentration (Cmax) for AZD4604 and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time 0 to the time of the last measurable concentration for AZD4604 and total radioactivity (AUC0-t) - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Area under the curve from time of the last measurable concentration to infinity as a percentage of the area under the curve extrapolated to infinity (AUCextrap) and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Terminal elimination half-life of AZD4604 (t1/2) and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• First order rate constant associated with the terminal (log-linear) portion of the curve for AZD4604 (λz) and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Total body clearance calculated after a single extravascular administration where F (fraction of dose bioavailable) is unknown (CL/F) - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single extravascular administration where F (fraction of dose bioavailable) is unknown (Vz/F) - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Renal clearance calculated using plasma AUC of AZD4604 and total radioactivity - Part 2

  PK of AZD4604 in plasma and whole blood

  Plasma and whole blood sample collection from pre-dose to 336 hours post-dose

• Assessment of metabolites in plasma, urine and faeces by liquid chromatography-radiochemical-detection and subsequent mass spectrometry - Part 2

  Metabolite profiling and structural identification from plasma, urine and faecal samples

  Plasma, urine and faces sample collection from pre-dose to 336 hours post-dose

Secondary Outcomes (5)

• Absolute bioavailability - Part 1

  Plasma sample collection from pre-dose to 336 hours post-dose

• Identification of the chemical structure of each metabolite accounting for more than 10% by AUC of circulating TR and/or accounting for 10% or more of the dose in excreta

  Urine and faecal sample collection from pre-dose to 336 hours post-dose

• Number of subjects with treatment-related adverse events - Part 1 and Part 2

  Through study duration, approximately 13 weeks

• Blood:plasma concentration ratios - Part 2

  Whole blood samples and plasma samples collected from pre-dose until 336 hours post-dose

• Absolute bioavailability - Part 2

  Plasma sample collection from pre-dose to 336 hours post-dose

Study Arms (1)

AZD4604

EXPERIMENTAL

In Part 1, one 30 ug dose of \[14C\]AZD4604 Solution for Infusion 6 ug/mL (NMT 37.0 kBq/5 mL) and one 3 mg dose of AZD4604 Inhalation Powder, 1 mg (as 3 x 1 mg). In Part 2, one 4 mg dose of \[14C\]AZD4604 Oral Solution, 4 mg (NMT 37.0 kBq).

Drug: AZD4604 Inhalation Powder, 1 mg; Drug: [14C]AZD4604 Solution for Infusion 6 μg/mL (NMT 37.0 kBq/5 mL); Drug: [14C]AZD4604 Oral Solution, 4 mg (NMT 37.0 kBq)

Interventions

AZD4604 Inhalation Powder, 1 mg DRUG

3 mg dose, inhaled, fasted

Also known as: AZD4604

AZD4604

[14C]AZD4604 Solution for Infusion 6 μg/mL (NMT 37.0 kBq/5 mL) DRUG

30 μg, intravenous, fasted

Also known as: AZD4604

AZD4604

[14C]AZD4604 Oral Solution, 4 mg (NMT 37.0 kBq) DRUG

4 mg, oral, fasted

Also known as: AZD4604

AZD4604

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures
• Must be willing and able to communicate and participate in the whole study
• Healthy males or non-pregnant, non-lactating healthy female subjects aged 18 to 65 years inclusive at the time of signing informed consent
• Females must have a negative serum pregnancy test at screening and a negative urine pregnancy test on admission to the unit, must not be lactating and not intending to become pregnant during their study participation, confirmed at screening and admission/pre-dose and fulfil the criteria detailed in the Clinical Protocol
• Must agree to adhere to the contraception requirements defined in the Clinical Protocol
• Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weight at least 50 kg and no more than 100 kg inclusive
• Must have regular bowel movements (i.e. average stool production of ≥1 and ≤3 stools per day)
• Screening/pre-dose FEV1 \>80% of the predicted value for their age, gender, height and race
• Screening/pre-dose FEV1/forced vital capacity (FVC) \>0.70

You may not qualify if:

• History of any clinically significant disease or disorder (e.g. cardiovascular pulmonary, GI, liver, renal, neurological, musculoskeletal ,endocrine, metabolic, malignant, psychiatric, major physical impairment, skin abnormalities and glucose metabolism abnormalities) 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
• History or presence of GI, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
• Subjects with a history of asymptomatic gall stones
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP
• 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 AZD4604. Hay fever is allowed unless it is active
• History of clinically significant cardiovascular, renal, hepatic, dermatological, chronic respiratory or GI disease, neurological or psychiatric disorder, as judged by the investigator
• Subjects with a milk or milk protein allergy
• Subjects who have had any malignancy or neoplastic disease (except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured)
• Subjects with history or any ongoing, chronic or recurrent infectious disease, herpes, or evidence of tuberculosis infection
• Subjects with risk factors for thrombosis or any history of thrombosis
• Subjects with a previous history of pneumonia (even if effectively treated)
• History of infantile bronchiolitis, a history of asthma, adverse reaction or allergy to the inhaled medication AZD4604 or any excipients
• Upper respiratory tract infection (excluding otitis media) within 14 days of first admission, or lower respiratory tract infection within the last 3 months
• Acute diarrhoea or constipation in the 7 days before the predicted first dosing date. If screening occurs \>7 days before the first dosing date, this criterion will be determined on first dosing date. Diarrhoea will be defined as the passage of liquid faeces and/or a stool frequency of greater than 3 times per day. Constipation will be defined as a failure to open the bowels less frequently than every other day.
• Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening

Sponsors & Collaborators

• AstraZeneca: lead
• Quotient Sciences: collaborator

Study Sites (1)

Research Site

Ruddington, NG11 6JS, United Kingdom

Location

MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Somasekhara Menakuru, MBBS, MS, MRCS, DPM, MFPM

  Quotient Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2023
• First Posted: December 5, 2023
• Study Start: February 16, 2024
• Primary Completion: May 20, 2024
• Study Completion: May 20, 2024
• Last Updated: May 29, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to teh EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-levels data in an approved sponsors tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the disclosure statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

GB (1)