This study is designed to describe the metabolism of AT1001 (migalastat HCl) and the contribution of metabolism and urinary excretion to its overall elimination as part of the continuing assessment of the safety and effectiveness of the drug. This is a Phase 1, single-site, open-label, single dose study of the absorption, metabolism and excretion of radiolabeled AT1001 in healthy male subjects between 30 and 55 years of age, inclusive. Six subjects will be dosed, with the goal of having at least 4 subjects complete the study through follow-up. All subjects will be screened within 28 days before admission to the Clinical Unit. Subjects will be confined to the clinical unit for 10 days after dosing and will return to the clinic for a follow-up visit 28 days after dosing. Each subject will receive a single oral dose of AT1001 as an aqueous solution containing 150 mg \[14C\] AT1001 (1 μCi). Blood, duodenal bile, expired air, urine, and feces samples will be collected at specified time points after dosing throughout the period of confinement at the study site. Safety will be assessed throughout the study by monitoring clinical laboratory tests, ECGs, physical examinations, vital signs, and adverse events. The total duration of the study for each subject is approximately 8 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
150 mg of \[14C\] labelled AT1001 will be administered as a solution (prepared by weighing 150 mg of AT1001 powder and dissolving in 100 mL of water). The entire solution will be swallowed orally. After ingestion of study medication, the dosing bottle will be rinsed with 50 mL of water and this will be ingested by the subject. This rinse procedure should be performed twice. Following the second rinse ingestion, the subjects should be instructed to drink additional water to bring the total volume ingested to 240 mL.
Recovery of total radioactivity in urine
Urine will be collected: pre-dose (-12-0 hours), 0-12 and 12-24 hours on Day 1, 24-hourly on Days 2-10; the last sample will be collected on Day 11. Total radioactivity excreted in urine will be calculated for the entire collection period. The excretion rate will be calculated from total radioactivity collected in urine, divided by the duration of collection. The percentage of dose excreted in urine will be calculated from the total amount excreted in urine divided by the dose administered, multiplied by 100.
Time frame: Days 1 to 11
Recovery of total radioactivity in feces
Feces will be collected: predose (-24 to 0 hours); all bowel movements post-dose will be collected on Days 1 to 10; the last sample will be collected on Day 11. Total radioactivity excreted in feces will be calculated for the entire collection period. The excretion rate will be calculated from total radioactivity collected in feces, divided by the duration of collection. The percentage of dose excreted in feces will be calculated from the total amount excreted in feces divided by the dose administered, multiplied by 100.
Time frame: Days 1 to 11
Presence of radioactivity in expired air
Expired air will be collected: pre-dose and at 2, 4, 6 and 24 hours after dosing. Each subject will blow into a measured volume of sodium hydroxide solution containing phenolphthalein, until an indicator changes color, showing that the sodium hydroxide is saturated. This sodium hydroxide solution will be analysed for radioactive content. If radioactivity is detected the total amount in expired air during the collection period will be calculated.
Time frame: Day 1
Plasma AT1001 pharmacokinetic parameters
Blood samples will be collected: Pre-dose, at 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216 and 240 hours after dosing. Non-compartmental pharmacokinetic parameters will be calculated for plasma AT1001: area under the drug concentration-time curve (AUC) from time zero to the time of the last measurable concentration, AUC from time zero to infinity, maximum observed drug concentration, time of the maximum drug concentration, apparent terminal elimination rate constant and apparent elimination half life.
Time frame: Days 1 to 10
Plasma total radioactivity pharmacokinetic parameters
Blood samples will be collected: Pre-dose, at 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216 and 240 hours after dosing. Non-compartmental pharmacokinetic parameters will be calculated for plasma radioactivity: area under the drug concentration-time curve (AUC) from time zero to the time of the last measurable concentration, AUC from time zero to infinity, maximum observed drug concentration, time of the maximum drug concentration, apparent terminal elimination rate constant and apparent elimination half life.
Time frame: Days 1 to 10
Number of subjects with adverse events as a measure of safety and tolerability
Adverse events (AEs) will be collected from the start of Investigation Product and until the follow-up visit.
Time frame: Day 1 to Day 29
Measure of clinical laboratory test values to access safety and tolerability
Clinical laboratory tests will include hematology, coagulation tests, clinical chemistry, urinalysis, drug and toxicology screen, Hepatitis A and HIV screen.
Time frame: Upto 8 weeks
Physical examination to access safety and tolerability
Physical examination results will be categorized as normal, abnormal clinically significant, or abnormal not clinically significant
Time frame: Upto 8 weeks
Measure of vital signs to access safety and tolerability
Vital sign measurements will include pulse, respiratory rate, blood pressure, and oral temperature). Subjects should be in a supine position for at least 5 minutes prior to taking measurements.
Time frame: Upto 8 weeks
Measure of ECG to access safety and tolerability
Electrocardiograph (ECG) is a machine that measures the electrical activity of the heart and records changes in the hearts' rhythm. All subjects will undergo ECG testing.
Time frame: Upto 8 weeks
The blood to plasma ratio of total radioactivity
The ratio of plasma to blood radioactivity will be calculated at 2, 4, 6 and 24 hours after administration of AT1001.
Time frame: Day 1
Characterization of metabolites in plasma, urine, duodenal bile and fecal homogenates
An Entero-Test capsule will be ingested to collect duodenal bile and will be removed after sample collection. Metabolite elucidation and identification will be performed in the collected plasma, urine doudenal bile, and fecal samples, if feasible, under a separate study. Results will be summarized in a separate report.
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Time frame: Day -1 to Day 11