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.
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. In this study, healthy volunteers will be given single doses of test medicine to find out how the body breaks down and gets rid of the test medicine. Two doses of the test medicine will be 'radiolabelled' - they will contain a small amount of radioactivity (Carbon-14) - so that it can be tracked in the body. 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. It plans to enrol 8 healthy men and women aged 18-65 years who will be involved in both parts of the study. In Part 1, volunteers will receive a dose of test medicine containing a very tiny amount of radio label, by injection into a vein, shortly followed by a single inhaled dose of the test medicine. In Part 2, volunteers will receive a dose of test medicine containing a very tiny amount of radio label, by mouth. In both parts volunteers will stay in the clinic for 15 nights, there will be a minimum 21 day washout period between each study part, and it will take up to 13 weeks to finish the study. A follow-up phone call will be conducted 6 to 10 days after discharge from Part 2. Blood and urine samples will be collected to do safety tests. Over a period of at least 15 days for each part, many blood samples will be taken and volunteers will collect all their urine and faeces so that the amount of test medicine and its breakdown products can be measured.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
8
3 mg dose, inhaled, fasted
30 μg, intravenous, fasted
4 mg, oral, fasted
Research Site
Ruddington, United Kingdom
Amount of AZD4604 excreted (Ae) - Part 1
Mass balance of total radioactivity (TR) of \[14C\]AZD4604 in urine and faeces
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Plasma, urine and faces sample collection from pre-dose to 336 hours post-dose
Absolute bioavailability - Part 1
Absolute bioavailability (Finh) based on AUC0-inf of inhaled administration compared to IV administration, adjusted for dose
Time frame: 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
Identification of chemical structure of each metabolite accounting for more than 10% of circulating TR or accounting for 10% more of the dose in urine and faeces
Time frame: 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
To provide additional safety and tolerability information for AZD4604 by assessing the incidence of AEs
Time frame: Through study duration, approximately 13 weeks
Blood:plasma concentration ratios - Part 2
Blood:plasma concentration ratios of total radioactivity
Time frame: Whole blood samples and plasma samples collected from pre-dose until 336 hours post-dose
Absolute bioavailability - Part 2
Absolute bioavailability (Finh) based on AUC0-inf of oral administration compared to IV administration, adjusted for dose
Time frame: Plasma sample collection from pre-dose to 336 hours post-dose
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