The purpose of this Phase I, open-label study is to evaluate the absorption, distribution, metabolism, excretion, absolute bioavailability, and to characterize the metabolites of AG-881 in healthy male participants following administration of a single oral dose of \[14C\] AG-881 and a concomitant intravenous microdose of \[13C315N3\] AG-881.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
5
Single oral dose of approximately 50 mg AG-881 (free form) containing approximately 100 microcuries (μCi) of \[14C\]AG-881.
Single IV microdose of approximately 100 μg.
Covance Clinical Research Unit Inc.
Madison, Wisconsin, United States
Amount of AG-881 Excreted in Urine (Aeu)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Aeu (Cum Aeu) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Percentage of AG-881 excreted in Urine and Feces (feu and fef, Respectively)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Percentage of AG-881 Excreted in Urine (Cum feu)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Cumulative Percentage of AG-881 Excreted in Feces (Cum fef)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Renal Clearance (CLR) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Renal Clearance Expressed as a Percentage of Total Clearance (CLR/CL) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Percentage of Total Radioactivity in Total Excreta Calculated as Cumulative Percentage of AG-881 Excreted in Urine and Feces (Cum fe)
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Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to 72 hours (AUC0-72) of AG-881
Time frame: Up to 72 hours
Partial Area Under the Concentration-time Curve from Time Zero to Common Time Point (AUC0-t) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Area Under the Concentration-time Curve from Time Zero to Infinity (AUC0-∞) of AG-881 Calculated Using the Observed Value of the Last Quantifiable Concentration
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Maximum Observed Plasma Concentration (Cmax) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Time to Maximum Observed Plasma Concentration (Tmax) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Terminal Elimination Half-life (t½) of AG-881
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
AUC0-∞ or AUC0-t of AG-881 in Plasma/AUC0-∞ or AUC0-t of Total Radioactivity in Plasma (AUC Plasma AG-881/Total Radioactivity Ratio)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
AUC0-∞ of Total Radioactivity in Whole Blood to AUC0-∞ of Total Radioactivity in Plasma (AUC Blood/Plasma Ratio), Calculated Using the Observed Value of the Last Quantifiable Concentration
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Total Clearance of AG-881 Following Intravenous (IV) Administration (CL)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Clearance Following Oral Administration of AG-881 (CL/F)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Volume of Distribution of AG-881 at Steady-state Following IV Administration (Vss)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Apparent Volume of Distribution During the Terminal Phase Following Oral Administration of AG-881 (Vz/F)
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Absolute bioavailability (F) for AG-881 Calculated as the Ratio of Dose-normalized AUC0-∞ of Oral/Intravenous Dosing
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Metabolic Profiles of AG-881 in Plasma, Urine, and Feces, When Possible
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Structures of AG-881 Metabolites in Plasma, Urine, and, Where Possible, Feces
Time frame: At multiple time points daily from Day -1 to Day 14; then at 24-hour intervals until discharge (up to 29 days); then weekly up to approximately 8 weeks
Percentage of Participants with Adverse Events (AEs), Graded by Severity
AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03)
Time frame: Up to approximately 12 weeks
Percentage of Participants with Laboratory Abnormalities
Laboratory assessments will include parameters assessing clinical chemistry, hematology, coagulation, urinalysis, and serology.
Time frame: Up to approximately 8 weeks
Percentage of Participants with Abnormalities in 12-lead Electrocardiogram (ECG)
Time frame: Up to approximately 8 weeks
Percentage of Participants with Abnormalities in Vital Signs Measurements
Vital signs will include supine blood pressure, supine pulse rate, and oral body temperature.
Time frame: Up to approximately 8 weeks
Percentage of Participants with Abnormalities in Physical Examinations
Time frame: Up to approximately 8 weeks