Bioavailability of [14C]-SK-1404 ADME & IV Microtracer Study

Study Overview
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Brief Summary
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The primary objectives of the study are: To determine the absolute bioavailability of SK-1404 To assess the mass balance recovery after a single oral (PO) dose of carbon-14 (14C)-SK-1404 To provide plasma, urine and faecal samples for metabolite profiling and structural identification The secondary objectives of the study are: To determine the routes and rates of elimination of [14C]-SK-1404 To identify the chemical structure of each metabolite with an exposure (AUC) of more than 10% of circulating total radioactivity To explore the intravenous (IV) pharmacokinetics (PK) of [14C]-SK-1404 To further explore the PO PK of SK-1404 To provide additional safety and tolerability information for SK-1404

Detailed Description
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This is a single-centre, 2-part, open-label, non-randomised, sequential, single dose study in healthy male subjects. It is planned to enrol a single cohort of 6 healthy male subjects who will participate in Parts 1 and Part 2 of the study. In Part 1, each subject will receive a single PO dose of SK-1404 followed by an IV microtracer dose of [14C]-SK-1404. In Part 2, each subject will receive a single PO dose of [14C]-SK-1404.

Official Title
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An Open-Label, 2-Part Sequential Dose Study Designed to Assess the Absolute Bioavailability, Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-SK-1404 Administered to Healthy Male Subjects

Conditions
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Nocturia

Intervention / Treatment
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* Drug: [14C]-SK-1404


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males Age 30 to 65 years of age Body mass index of 18.0 to 35.0 kg/m2 or, if outside the range, considered not clinically significant by the investigator Must be willing and able to communicate and participate in the whole study Must provide written informed consent Must have regular bowel movements (ie average stool production of ≥1 and ≤3 stools per day) Must agree to use an adequate method of contraception Exclusion Criteria: Males with pregnant partners Participation in a clinical research study within the 3 months prior to IMP dose 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 Subjects who have previously been dosed with SK-1404 History of any drug or alcohol abuse in the past 2 years Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine) in the past year Current smokers and those who have smoked within the last 12 months; this includes cigarettes, e-cigarettes and nicotine replacement products. A breath carbon monoxide reading of greater than 10 ppm at screening or admission 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 1999, shall participate in the study Subjects who have been enrolled in an ADME study in the last 12 months Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator (laboratory parameters are listed in Appendix 1) Aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase >1.5 × upper limit of normal confirmed by repeat testing Serum sodium below the lower limit of normal

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: [14C]-SK-1404<br> | Drug: [14C]-SK-1404<br>* In Part 1, each subject will receive a single PO dose of SK-1404 followed by an IV microtracer dose of [14C]-SK-1404.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute bioavailability (F) calculated with the AUC values of IV administration in Part 1 and PO administration in Part 2 |  | Predose to 96hr | 
| Mass balance recovery of total radioactivity in urine, faeces and all excreta | Amount excreted (Ae), and Ae as a percentage of the administered dose (%Ae), cumulative recovery (Cum Ae) and cumulative recovery expressed as a percentage of the dose (Cum %Ae) | Predose to 168hr | 
| Number and structural identification of known and unknown metabolites of SK-1404 in the plasma, urine and faeces samples |  | Predose to 168hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ae total radioactivity in plasma by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| %Ae total radioactivity in plasma by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| Cum Ae (total) for urine by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| Cum %Ae (total) for urine by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| Cum Ae (total) for faeces by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| Cum %Ae (total) for faeces by metabolite profiling and structural identification to estimate the routes and rates of elimination of [14C]-SK-1404 |  | Predose to 168hr | 
| Number and structural identification of unknown metabolites of SK-1404 with an AUC of more than 10% of circulating total radioactivity |  | Predose to 168hr | 
| The peak plasma concentration (Cmax) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The time from dosing at which Cmax was apparent (Tmax) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The elapsed time from dosing at which the analyte was first quantifiable in a concentration vs time profile (Tlag) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The area under the concentration-time curve from dosing to the last measurable concentration (AUC(0-last)) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The area under the concentration-time curve from dosing extrapolated to infinity (AUC(0-inf)) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The percentage of AUC(0-inf) extrapolated beyond the last measured time point (AUC%extrap) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The terminal elimination rate constant calculated from the slope of the apparent elimination phase (lambda-z) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The apparent terminal elimination half-life (T1/2) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The apparent total clearance (CL/F) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The apparent volume of distribution (Vd) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The apparent volume of distribution (Vss) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The mean residence time (MRT) of SK-1404F and its active metabolites M-1, M-7 and M-9) after IV SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 96hr | 
| The peak plasma concentration (Cmax) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The time from dosing at which Cmax was apparent (Tmax) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The elapsed time from dosing at which the analyte was first quantifiable in a concentration vs time profile (Tlag) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The area under the concentration-time curve from dosing to the last measurable concentration (AUC(0-last)) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The area under the concentration-time curve from dosing extrapolated to infinity (AUC(0-inf)) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The percentage of AUC(0-inf) extrapolated beyond the last measured time point (AUC%extrap) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The terminal elimination rate constant calculated from the slope of the apparent elimination phase (lambda-z) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The apparent terminal elimination half-life (T1/2) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The absolute bioavailability (F, PO vs IV from Part 1) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The apparent total clearance (CL/F) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The apparent volume of distribution (Vd/F) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| The mean residence time (MRT) of SK-1404F and its active metabolites M-1, M-7 and M-9) after PO SK-1404 | Metabolite:parent ratios will be calculated for SK-1404F, M-1, M-7 and M-9 | Predose to 168hr | 
| To collect further information about the safety and tolerability of IMP | By assessing physical examination, safety laboratory tests, vital signs, electrocardiograms (ECGs) and AEs. | Predose to 168hr | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nocturnal polyuria