This is a single-center, 2-part, open-label study to evaluate the metabolism and excretion and absolute bioavailability of \[14C\]-AG-221 in healthy male subjects. It is planned for 14 subjects to be enrolled; each subject will participate in a screening phase, a baseline phase, a treatment phase, and a follow up phone call. Blood, urine and fecal samples will be collected in Part 1 for analyses. Blood samples will be collected in Part 2. Subjects can only participate in either Part 1 or Part 2.
This will be a single-center, open-label, 2-part study in healthy adult males (n = 14). Parts 1 and 2 may be conducted in parallel. Each subject will participate in a screening phase, a baseline phase, a treatment phase, and a follow up phone call. Subjects who have met all inclusion criteria and none of the exclusion criteria at screening will return to the clinical site on Day 1 for baseline assessments. Part 1: Absorption, metabolism, and excretion (AME) Approximately 8 subjects will be enrolled in Part 1. Subjects will check into the clinic on the day before dosing. Following a 10 hour overnight fast, subjects will receive a single 100-mg dose of AG-221 solution containing a microtracer of \[14C\] AG 221 (\~ 300 nCi) under fasted conditions. The study drug will be administered as an oral solution with approximately 240 mL of room temperature, non-carbonated water. Blood, urine, and fecal samples (and vomitus, if applicable) will be collected throughout the study for pharmacokinetic (PK), mass balance, and/or clinical laboratory assessments. Safety will be monitored throughout the study. Subjects will be discharged from the clinical site on Day 22 following completion of the required study procedures. Subjects will return to the unit on Day 29 for the last PK blood draw. Urine and fecal samples will be collected each day until Day 22 (or the point of discharge if earlier) for measurement of total \[14C\] radioactivity. Blood samples for radioanalysis and PK assessment, inclusive of metabolite profiling/characterization, will be collected at pre-dose and at specified intervals through Day 29. Total \[14C\]-radioactivity in whole blood, plasma, urine, and feces (and vomitus, if applicable ) will be determined. Part 2: Absolute bioavailability: Approximately 6 subjects will be enrolled in Part 2. Qualified subjects who have met all inclusion criteria and none of the exclusion criteria at screening will return to the clinical site on Day 1, and will be housed at the clinical site from Day 1 until Day 3. After an overnight fast of at least 10 hours, approximately 6 subjects will receive an oral dose (coated tablet) of 100 mg of AG-221 at Hour 0 on dosing day (Day 1). The study drug will be administered orally with approximately 240 mL of water. Four hours after the oral dose, the subjects will receive 100 micrograms AG-221 containing \~300 nCi of \[14C\]-AG-221administered as an intravenous bolus over approximately 2 minutes. Subjects will be discharged from the unit upon completion of the 48 hour PK blood draw on Day 3. Subjects will return to the unit for additional PK blood draws on Days 5, 8, 11, 15, 18, 22, and 29. No urine and fecal samples will be collected in Part 2.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
NONE
Enrollment
8
Part 1: oral solution containing 100 mg \[14C\]-AG-221
5 mL of 100 micrograms \[14C\] AG-221 given intravenously 4 hours after swallowing the formulated tablet.
Pharmacokinetics - Total [14C] Whole blood and plasma
Total \[14C\]-radioactivity in whole blood and plasma
Time frame: Approximately 3 weeks
Pharmacokinetics - Total [14C] urine and feces
Total \[14C\]-radioactivity in urine, and feces (and vomitus, if applicable).
Time frame: approximately 3 weeks
Pharmacokinetics - Total [14C] Cumulative excretion
Cumulative excretion of total \[14C\]-radioactivity (as a fraction of the radioactive dose) in urine and feces (and vomitus, if applicable)
Time frame: approximately 3 weeks
Pharmacokinetics - Total [14C] radioactivity
Total \[14C\]-radioactivity whole blood-to-plasma ratios
Time frame: approximately 4 weeks
Pharmacokinetics - Total [14C] metabolites
Metabolite profiling / characterization in select plasma, urine, and fecal samples
Time frame: approximately 3 weeks
Pharmacokinetics: Metabolite profiling and characterization in select biological matrices (Part 1)
The analysis for metabolite profiles and characterization are qualitative and there are no units for the analysis.
Time frame: approximately 4 weeks
Pharmacokinetics - Cmax
Maximum observed plasma concentration
Time frame: approximately 4 weeks
Pharmacokinetics - AUC
Area under the plasma concentration-time curve
Time frame: approximately 4 weeks
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Pharmacokinetics - Tmax
Time to maximum observed plasma concentration
Time frame: approximately 4 weeks
Pharmacokinetics -T1/2
Estimate of the terminal elimination half-life
Time frame: approximately 4 weeks
Adverse Events (AEs)
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study.
Time frame: approximately 8 weeks