Study to Evaluate the Potential Pharmacokinetic Interaction and Pharmacodynamic Effects on Renal Parameters of Bumetanide (1mg) and Dapagliflozin (10 mg) When Co-administered in Healthy Subjects

• To assess the safety and tolerability of bumetanide and dapagliflozin following multiple oral doses of 1 mg bumetanide and 10 mg dapagliflozin, administered together, either simultaneously or after adaptation to either agent alone, in healthy subjects [ Time Frame: during 14 days of dosing ] [ Designated as safety issue: Yes ]
• Explore potential pharmacodynamic (serum/urine electrolytes) effects of bumetanide + dapagliflozin following multiple doses of 1 mg bumetanide + 10 mg dapagliflozin, administered together, either simultaneously or after adaptation to either agent alone [ Time Frame: during 14 days of dosing ] [ Designated as safety issue: Yes ]

To assess the potential pharmacokinetic (PK) interactions of bumetanide and dapagliflozin following multiple doses of 1 mg bumetanide and 10 mg dapagliflozin in healthy subjects

• Drug: Bumetanide
  Tablets, Oral, 1 mg, Single Dose, 7 Days
  Other Name: Bumex
• Drug: Dapagliflozin
  Tablets, Oral, 10 mg. Single Dose, 7 Days
  Other Name: BMS-512148

• Active Comparator: Bumetanide
  Intervention: Drug: Bumetanide
• Active Comparator: Dapagliflozin
  Intervention: Drug: Dapagliflozin
• Active Comparator: Bumetanide + Dapagliflozin
  Interventions:

  • Drug: Bumetanide
  • Drug: Dapagliflozin

Inclusion Criteria:

• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations
• Body Mass Index (BMI) of 18 to 32 kg/m², inclusive. BMI = weight (kg)/ [height (m)]²
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized and men, ages 18 to 45

Exclusion Criteria:

• WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
• Any significant acute or chronic medical illness
• Current or recent (within 3 months) gastrointestinal disease
• Current smoker or recent (within 1 month) history of regular tobacco use
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population
• Abnormal urinalysis at screening
• Glucosuria at screening
• Abnormal liver functions tests (ALT, AST or total bilirubin > 10 % ULN)
• Presence of edema on physical exam
• History of diabetes mellitus
• History of heart failure
• History of renal insufficiency
• History of chronic or recurrent UTI (defined as 3 occurrences per year) or UTI in the past 3 months
• Positive urine screen for drugs of abuse either at screening or before dosing
• Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, or HIV-1, -2 antibody
• History of allergy to SGLT2 inhibitors, bumetanide (or related compounds)
• History of any significant drug allergy (such as anaphylaxis or hepatotoxicity)
• Prior exposure to dapagliflozin within 3 months of Day -1
• Exposure to any investigational drug or placebo within 4 weeks of Day -1
• Use of any prescription drugs within 4 weeks or over-the-counter acid controllers within 2 weeks prior to study drug administration
• Use of any other drugs, including over-the-counter medications within 1 week and herbal preparations, within 2 weeks prior to study drug administration
• Use of an oral, injectable or implantable hormonal contraceptive agent within 3 months of study drug administration