Bexagliflozin Drug/Drug Interaction Study With Digoxin

This was a phase 1, single center, open-label, two-period, two-treatment, crossover study to evaluate the effect of bexagliflozin tablets, 20 mg, on the pharmacokinetics (PK) of digoxin, 0.5 mg after co-administration in healthy subjects. Each subject was randomized into one of 2 treatment groups and participated in 2 treatment periods as outlined below. During the duration of the study, each subject received 8 single doses of bexagliflozin and 2 single doses of digoxin. Clinical laboratory tests and safety monitoring were conducted during Periods 1 and 2.

Group 1 - Period 1, Treatment A Subjects were admitted to the clinic on Day 0. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, starting on Day 1 for 8 days, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 3. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), and 120 h (Day 8) after administration of digoxin. Subjects were discharged on Day 8.

Group 1 - Period 2, Treatment B Subjects were admitted to the clinic on Day 18. On Day 19, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), and 120 h (Day 24) after administration of digoxin. Subjects were discharged on Day 24.

Group 2 - Period 1, Treatment B Subjects were admitted to the clinic on Day 0. On Day 1, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 1, 24 h (Day 2), 48 h (Day 3), 72 h (Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of digoxin. Subjects were discharged on Day 6.

Group 2 - Period 2, Treatment A Subjects were admitted to the clinic on Day 14. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 17. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 17, 24 h (Day 18), 48 h (Day 19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 22) after administration of digoxin. Subjects were discharged on Day 22.

• Bexagliflozin (Drug), also known as EGT0001442, EGT0001474: Bexagliflozin tablets, 20 mg
• Digoxin (Drug): 2 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)

Primary outcomes

• Digoxin Cmax (Maximum Observed Plasma Concentration) [Up to 120 hours]: Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
• Digoxin Tmax (Time of Maximum Observed Plasma Concentration) [Up to 120 hours]: Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
• Digoxin T1/2 (Apparent Terminal Elimination Half-life) [Up to 120 hours]: Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
• AUC0-inf (Area Under the Plasma Concentration-time Curve From Time 0 to Infinity) [Up to 120 hours]: Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

1. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2
2. Subjects who are non-smokers for at least 6 months prior to first dose
3. Subjects who are willing to use an adequate form of birth control during the study and for 30 days after discharge from clinic

Exclusion Criteria:

1. Subjects with a clinically significant history of allergy to drugs or latex
2. Subjects with a history of alcohol or drug dependence in the past 12 months
3. Subjects who have donated a significant amount of blood in the past 2 months
4. Subjects who have taken an investigational drug in the past 30 days or 7 half-lives of the investigational drug, whichever is longer
5. Subjects who had previously received digoxin or drugs of the same class, or SGLT2 inhibitors, in the past 3 months

Participant flow

Outcome results

• Digoxin Cmax (Maximum Observed Plasma Concentration) (Primary), Geometric mean, ng/mL: Digoxin Alone 2.315 +/- 28.8; Digoxin With Bexagliflozin 2.301 +/- 40.9
• Digoxin Tmax (Time of Maximum Observed Plasma Concentration) (Primary), Median, hours: Digoxin Alone 1.00 (1 to 2); Digoxin With Bexagliflozin 1.00 (1 to 4)
• Digoxin T1/2 (Apparent Terminal Elimination Half-life) (Primary), Geometric mean, hours: Digoxin Alone 34.3 +/- 15.5; Digoxin With Bexagliflozin 38.2 +/- 15.7
• AUC0-inf (Area Under the Plasma Concentration-time Curve From Time 0 to Infinity) (Primary), Geometric mean, h*ng/mL: Digoxin Alone 35.558 +/- 16.6; Digoxin With Bexagliflozin 37.805 +/- 27.5

Adverse events

Time frame: Adverse event data were collected from Day 0 up to Day 24 of the study

Other adverse events by term

• Study Protocol (PDF, 2017-06-13)
• Statistical Analysis Plan (PDF, 2017-10-18)

• Mason Freeman, M.D., Study director, Massachusetts General Hospital