Clinical trial NCT00930865: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2009-07-02
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: 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

Primary outcomes:
measure: Exposure to the investigational drug will be measured to compare with and without the co-administration of other drugs
timeFrame: 24 hours post-dose on Day 8 and 15
Secondary outcomes:
measure: 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
timeFrame: during 14 days of dosing
measure: 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
timeFrame: during 14 days of dosing
Other outcomes:
Locations:
city: Austin
country: United States
facility: Ppd Development, Lp
state: Texas
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Wilcox CS, Shen W, Boulton DW, Leslie BR, Griffen SC. Interaction Between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects. J Am Heart Assoc. 2018 Feb 10;7(4):e007046. doi: 10.1161/JAHA.117.007046.