A Study Designed to Assess the Mass Balance Recovery, Absorption, Metabolism, Excretion of [14C]AZD5462 and the Absolute Bioavailability of AZD5462

AstraZeneca8 enrolled

Overview

A study to investigate how the body breaks down and gets rid of the test medicine, AZD5462. To help investigate this, the test medicine is radiolabelled, which means that the test medicine has a radioactive component (carbon-14), which helps us to track where the test medicine is in the body. The safety and tolerability of the test medicine will also be studied.

This is an open-label, two-period study designed to assess the mass balance recovery, absorption, metabolism, excretion of \[14C\]AZD5462 and the absolute bioavailability of AZD5462 in healthy male participants. The study will take place at 1 site in Nottingham, and enrol 8 healthy men aged 30-65 years. The study will include 2 Periods: * In Period 1 volunteers will receive a single dose of radiolabelled test medicine as a liquid by mouth. * In Period 2 volunteers will receive a single dose of the test medicine as capsules by mouth and shortly afterwards, a very tiny dose of radiolabelled study medicine by injection into a vein. The participants will be resident in the clinical unit throughout both study periods for a total of 12 nights. The total study duration is approximately up to 6 weeks.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Heart Failure

Interventions

AZD5462 film-coated tabletDRUG

Oral, fasted

[14C]AZD5462 Solution for InfusionDRUG

Intravenous, fasted

[14C]AZD5462 Oral SolutionDRUG

Oral, fasted

Eligibility

Sex: MALEMin age: 30 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy males aged 30 to 65 years inclusive * BMI in the range 18.0 - 32.0 kg/m2 inclusive and body weight ≥ 50 kg and ≤ 100 kg * Regular bowel movements (i.e. average stool production of ≥1 and ≤3 stools per day) Exclusion Criteria: * History of any clinically significant disease or disorder * 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 * History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity * History of active malignancy within 2 years, or under investigation for any form of cancer * Participants who do not have suitable veins for multiple venepunctures/cannulation * Clinically significant abnormal clinical chemistry, haematology or urinalysis * Any clinically significant abnormalities in vital signs * Any clinically significant abnormalities on 12-lead ECG * Abnormal renal function * Radiation exposure exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years, occupationally exposed worker, or have been administered IMP in a radiolabelled ADME study in the last 12 months. * Use of any prescribed or non-prescribed medication including antacids, analgesics, herbal remedies, vitamins and minerals * Current smokers or known or suspected history of alcohol or drug abuse * Excessive intake of caffeine-containing drinks or food

Locations (1)

Research Site

Ruddington, United Kingdom

Outcomes

Primary Outcomes

Amount of AZD5462 excreted (Ae) - Period 1

Mass balance recovery of total radioactivity of \[14C\]AZD5462 in urine and faecal samples

Time frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose

Amount of AZD5462 excreted expressed as a percentage of the dose administered (Fe) - Period 1

Mass balance recovery of total radioactivity of \[14C\]AZD5462 in urine and faecal samples

Time frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose

Cumulative amount of AZD5462 excreted (CumAe) - Period 1

Mass balance recovery of total radioactivity of \[14C\]AZD5462 in urine and faecal samples

Time frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose

Cumulative amount of AZD5462 excreted expressed as a percentage of the dose administered (CumFe) - Period 1

Mass balance recovery of total radioactivity of \[14C\]AZD5462 in urine and faecal samples

Time frame: Urine and faecal samples collected from pre-dose until 168 hours post-dose

Absolute bioavailability - Period 2

Absolute bioavailability (F) based on AUC0-inf of oral and IV administration, adjusted for dose

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Secondary Outcomes

Time of maximum observed concentration (tmax) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Data from ClinicalTrials.gov

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Maximum observed concentration (Cmax) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Area under the curve from time 0 to the time of last measurable concentration (AUC0-t) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 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 (AUC0-extrap) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Terminal elimination half-life (t1/2) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

First order rate constant associated with the terminal (log-linear) portion of the curve (λz) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Total body clearance calculated after a single extravascular administration where F (fraction of dose bioavailable) is unknown (CL/F) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Renal clearance calculated using plasma AUC (CLR) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma and urine

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Apparent 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) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma and urine

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Area under the curve (AUC) of circulating plasma total radioactivity (TR) or accounting for 10% or more of the dose in excreta - Period 1

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

Time frame: Plasma, urine and faecal samples from pre-dose until 168 hours post-dose

Blood:plasma concentration ratios - Period 1

Blood:plasma concentration ratios of total radioactivity

Time frame: Whole blood samples and plasma samples collected from pre-dose until 168 hours post-dose

Amount of unchanged AZD5462 excreted in urine (Ae) - Period 2

Recovery of total radioactivity of \[14C\]AZD5462 in urine

Time frame: Urine sample collection from pre-dose to 72 hours post-dose

Amount of unchanged AZD5462 excreted in urine expressed as a percentage of the radioactive dose administered (Fe) - Period 2

Recovery of total radioactivity of \[14C\]AZD5462 in urine

Time frame: Urine sample collection from pre-dose to 72 hours post-dose

Cumulative amount of unchanged AZD5462 excreted in urine (CumAe) - Period 2

Recovery of total radioactivity of \[14C\]AZD5462 in urine

Time frame: Urine sample collection from pre-dose to 72 hours post-dose

Cumulative amount of unchanged AZD5462 excreted in urine expressed as a percentage of the radioactive dose administered (CumFe) - Period 2

Recovery of total radioactivity of \[14C\]AZD5462 in urine

Time frame: Urine sample collection from pre-dose to 72 hours post-dose

Area under the curve from time 0 extrapolated to infinity (AUC0-inf) for AZD5462 and total radioactivity - Period 1

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 168 hours post-dose

Time of maximum observed concentration (tmax) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Maximum observed concentration (Cmax) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Area under the curve from time 0 extrapolated to infinity (AUC0-inf) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Area under the curve from time 0 to the time of last measurable concentration (AUC0-t) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Terminal elimination half-life (t1/2) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

First order rate constant associated with the terminal (log-linear) portion of the curve (λz) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Total body clearance calculated after a single IV administration (CL) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Total body clearance calculated after a single extravascular administration where F (fraction of dose bioavailable) is unknown (CL/F) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Volume of distribution based on the terminal phase calculated using AUC(0-inf) after a single IV administration (Vz) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

Apparent volume of distribution at steady state after a single IV administration (Vss) for AZD5462 and [14C]AZD5462 - Period 2

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

PK of AZD5462 and \[14C\]AZD5462 in plasma

Time frame: Plasma sample collection from pre-dose to 72 hours post-dose

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

To provide additional safety and tolerability information for AZD5462

Time frame: Through study duration, an average of 7 weeks