Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-MD1003 in Healthy Male Subjects

Study Overview
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Brief Summary
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This single-center, open-label, non randomized Phase I study is being conducted to investigate the pharmacokinetics, mass balance and metabolite profiling and identification after a single oral dose of 100mg of [14C]-MD1003 in 6 healthy males subjects. The radioactivity will be followed in the blood, urine and faeces to study MD1003 metabolism.

Official Title
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An Open-Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-MD1003 in Healthy Male Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: [14C]-MD1003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males Age 30 to 65 years of age at the time of signing informed consent Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening Must be willing and able to communicate and participate in the whole study Must have regular bowel movements (ie average stool production of ≥1 and ≤3 stools per day) Must provide written informed consent Must agree to adhere to the contraception requirements of the protocol Exclusion Criteria: Subjects who have received any IMP in a clinical research study within the 90 days prior to Day 1 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 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, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type) A confirmed positive alcohol breath test at screening or admission Current smokers and those who have smoked within the last 12 months. A confirmed breath carbon monoxide reading of greater than 10 ppm at screening or admission Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months Subjects with pregnant or lactating partners 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 do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening Clinically significant abnormal clinical chemistry, haematology or urinalysis as judged by the investigator. Subjects with Gilbert's Syndrome are allowed Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in the protocol) Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results Evidence of renal impairment at screening, as indicated by an estimated creatinine clearance of <80 mL/min using the Cockcroft-Gault equation History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active Donation or loss of greater than 400 mL of blood within the previous 3 months Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than 4 g of paracetamol per day), herbal remedies, vitamin B5 or dietary supplements containing lipoic acid in the 14 days before IMP administration. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as determined by the PI Subjects who have had any intake of biotin (including as a nutritional supplement) in the 14 days before IMP administration Failure to satisfy the investigator of fitness to participate for any other reason

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: Health Services Research
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MD1003<br>radiolabeled 14C MD1003 (High Dose Biotin) 100mg | Drug: [14C]-MD1003<br>* single oral dose of 100mg [14C]-MD1003<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mass Balance Recovery of Total Radioactivity: CumAe (Urine) | Cumulative amount of total radioactivity excreted in urine Measured at 0/12/24/48/72/96/120/144/168/192/216/240/264/288/312 hours | Pre-dose to 312 hours post-dose | 
| Mass Balance Recovery of Total Radioactivity: Cum%Ae (Urine) | Cumulative amount of total radioactivity excreted in urine expressed as a percentage of the radioactive dose administered Measured at 0/0.5/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168/192/216/240/264/288/312 hours. | Pre-dose to 312 hours post dose | 
| Mass Balance Recovery of Total Radioactivity: CumAe (Faeces) | Cumulative amount of total radioactivity excreted in faeces Measured at 0/0.5/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168/192/216/240/264/288/312 hours. | Pre-dose to 312 hours post-dose | 
| Mass Balance Recovery of Total Radioactivity: Cum%Ae (Faeces) | Cumulative amount of total radioactivity excreted in faeces expressed as a percentage of the radioactive dose administered Measured at 0/0.5/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168/192/216/240/264/288/312 hours. | Pre-dose to 312 hours post dose | 
| Mass Balance Recovery of Total Radioactivity: CumAe(Total) | Cumulative amount of total radioactivity excreted in urine and faeces combined Measured at 0/0.5/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168/192/216/240/264/288/312 hours. | Pre-dose to 312 hours post dose | 
| Mass Balance Recovery of Total Radioactivity: Cum%Ae (Total) | Cumulative amount of total radioactivity excreted in urine and faeces combined expressed as a percentage of the radioactive dose administered Measured at 0/0.5/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168/192/216/240/264/288/312 hours. | Pre-dose to 312 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Prior to the First Measurable Concentration (Tlag) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Time of Maximum Plasma Concentration (Tmax) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Maximum Plasma Concentration (Cmax) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Area Under Plasma Concentration Curve From 0 Time to Last Measurable Concentration (AUC(0-last)) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Area Under Plasma Concentration Curve From 0 Time Extrapolated to Infinity (AUC(0-inf)) for MD1003 and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Percentage of AUC(0-extrap) Extrapolated Beyond the Last Measurable Concentration for MD1003 and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Area Under Plasma Concentration Curve From 0 Time to Last Measurable Concentration (AUC(0-12)) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Lambda-z for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Plasma Clearance (CL/F) for MD1003 | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Plasma Clearance (Vz/F) for MD1003 | Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Elimination Half Life (t1/2) for MD1003, Bisnorbiotin, Biotin Sulfoxide and Total Radioactivity | Measured at 0//1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| MPR Cmax for Bisnorbiotin and Biotin Sulfoxide | MPR = metabolite to parent ratio Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| MPR AUC(0-inf) for Bisnorbiotin and Biotin Sulfoxide | MPR = metabolite to parent ratio Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours | 
| Whole Blood: Plasma Concentration Ratios of Total Radioactivity | Total radioactivity in whole blood versus total radioactivity in plasma concentration ratios at time intervals following a single oral administration of 100mg [14C]-MD1003 Measured at 0/1/1.5/2/3/4/6/8/12/18/24/36/48/72/96/120/144/168 hours. | Pre-dose to 168 hours post-dose | 
| Number of Subjects With Adverse Events (AEs) | 2 months | Overall period | 
| Number of Subjects With Adverse Drug Reactions as Assessed by Investigator |  | Overall period | 
| Change From Baseline in Systolic Blood Pressure in mmHg | Change from baseline measure (defined as Day 1, pre-dose). Measured at screening/Pre-dose/1/4/24/72/168 hours. | Pre-dose to Day 10 | 
| Change From Baseline in Diastolic Blood Pressure in mmHg | Change from baseline measure (defined as Day 1, pre-dose). Measured at screening/Pre-dose/1/4/24/72/168 hours. | Pre-dose to Day 10 | 
| Change From Baseline in Heart Rate in Beats Per Minute | Change from baseline measure (defined as Day 1, pre-dose). Measured at screening/Pre-dose/1/4/24/72/168 hours. | Pre-dose to Day 10 | 
| Change From Baseline in ECG (Electrocardiogram) QTcF Interval in Milliseconds | Change from baseline measure (defined as Day 1, pre-dose). Measured at screening/Pre-dose/1/4/24/72/168 hours. | Pre-dose to Day 10 |