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

Study Overview
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Brief Summary
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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

Official Title
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A Randomized, Open-Label, Parallel-group, Multiple-Dose 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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Bumetanide
* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bumetanide<br> | Drug: Bumetanide<br>* Tablets, Oral, 1 mg, Single Dose, 7 Days<br>* Other names: Bumex;|
| Active Comparator: Dapagliflozin<br> | Drug: Dapagliflozin<br>* Tablets, Oral, 10 mg. Single Dose, 7 Days<br>* Other names: BMS-512148;|
| Active Comparator: Bumetanide + Dapagliflozin<br> | Drug: Bumetanide<br>* Tablets, Oral, 1 mg, Single Dose, 7 Days<br>* Other names: Bumex;Drug: Dapagliflozin<br>* Tablets, Oral, 10 mg. Single Dose, 7 Days<br>* Other names: BMS-512148;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exposure to the investigational drug will be measured to compare with and without the co-administration of other drugs |  | 24 hours post-dose on Day 8 and 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | during 14 days of dosing | 
| 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 |  | during 14 days of dosing |