Bioequivalence, Fixed Dose Combination Tablets, Healthy Male and Female Subjects
Conditions
Keywords
dapagliflozin/metformin XR 5/500 mg, dapagliflozin/metformin XR10/1000 mg, bioequivalence, fixed dose combination tablets, pharmacokinetic, type 2 Diabetes Mellitus (T2DM), safety
Brief summary
This is a bioequivalence study to compare 2 fixed-dose combination tablets of dapagliflozin/metformin XR manufactured at 2 different plants in healthy subjects under fasting and fed conditions
Detailed description
This is a Phase 1, 2-part, open-label, randomized, 4-period, 4-treatment, crossover study in healthy subjects (males and females of non-childbearing potential)
Interventions
DRUGdapagliflozin/metformin XR 5/500 mg test drug (Mount Vernon)
single fixed-combination dose tablets
DRUGdapagliflozin/metformin XR 5/500 mg reference drug (Humacao)
single fixed-dose combination tablets
DRUGdapagliflozin/metformin XR 10/1000 mg test drug (Mount Vernon)
single fixed-dose combination tablets
DRUGdapagliflozin/metformin XR 10/1000 mg reference drug (Humacao)
single fixed-dose combination tablets
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated, written informed consent prior to any study specific procedures 2. Healthy male and female subjects aged 18 - 55 years with suitable veins for cannulation or repeated venipuncture 3. Females must have a negative serum pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: * Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range * Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation 4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive at screening
Exclusion criteria
1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study 2. History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs 3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product 4. Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator 5. Any clinically significant abnormal findings in vital signs, as judged by the investigator 6. Any clinically significant abnormalities on 12-lead ECG as judged by the investigator 7. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody 8. Known or suspected history of drug abuse, as judged by the investigator 9. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose. 10. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening 11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to dapagliflozin/metformin XR. 12. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening 13. Positive screen for drugs of abuse, cotinine or alcohol at screening or on each admission to the study center 14. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP 15. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life 16. Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by the investigator 17. Involvement of any AstraZeneca or study site employee or their close relatives 18. Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements 19. Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state. |
| AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state |
| Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (t Max) | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. |
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. |
| Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. |
| Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at PAREXEL International, Early Phase Clinical Unit Baltimore, United States of America. Subjects were randomized into 4-period, 4-treatment (per study part) crossover (4 sequences containing 4 treatments) in fed and fasted state.
Pre-assignment details
Sequences 1, 2, 3 and 4 Part 1: ABCD, BADC, ABDC, BACD Part 2: EFGH, FEHG, EFHG, FEGH (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted; E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) A total of 80 subjects were randomized into the study
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Sequences 1, 2, 3 and 4- each sequence had 10 subjects; Part 1: ABCD, BADC, ABDC, BACD (A = test, fed; B = reference, fed; C = test, fasted; D = reference, fasted) Part 1: Test: Dapagliflozin/metformin XR mg manufactured at Mount Vernon plant (1 x 5/500 mg); Reference: Dapagliflozin/metformin XR mg manufactured at Humacao plant (1 x 5/500 mg) | 40 |
| Part 2 Sequences 1, 2, 3 and 4 - each sequence had 10 subjects Part 2: EFGH, FEHG, EFHG, FEGH (E = test, fed; F = reference, fed; G = test, fasted; H = reference, fasted) Part 2: Test: Dapagliflozin/metformin XR manufactured at Mount Vernon plant (1 x 10/1000 mg); Reference: Dapagliflozin/metformin XR manufactured at Humacao plant (1 x 10/1000 mg) | 40 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Positive drug screen at admission | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Part 1 | Part 2 | Total |
|---|---|---|---|
| Age, Continuous | 35.4 Years STANDARD_DEVIATION 10.38 | 38.1 Years STANDARD_DEVIATION 9.71 | 36.5 Years STANDARD_DEVIATION 10.04 |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 39 Participants | 37 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 40 | 5 / 38 | 1 / 37 | 2 / 36 | 2 / 39 | 4 / 40 | 4 / 39 | 3 / 39 |
| serious Total, serious adverse events | 0 / 40 | 0 / 38 | 0 / 37 | 0 / 36 | 0 / 39 | 0 / 40 | 0 / 39 | 0 / 39 |
Outcome results
Primary
Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State
To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state.
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 5484 h*ng/mL | Geometric Coefficient of Variation 24.69 |
| Treatment A | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 236.3 h*ng/mL | Geometric Coefficient of Variation 21.06 |
| Treatment B | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 5465 h*ng/mL | Geometric Coefficient of Variation 27.87 |
| Treatment B | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 248.6 h*ng/mL | Geometric Coefficient of Variation 20.79 |
| Treatment C | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 4398 h*ng/mL | Geometric Coefficient of Variation 29.41 |
| Treatment C | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 251.6 h*ng/mL | Geometric Coefficient of Variation 21.2 |
| Treatment D | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 258.2 h*ng/mL | Geometric Coefficient of Variation 18.35 |
| Treatment D | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 4460 h*ng/mL | Geometric Coefficient of Variation 29.69 |
| Treatment E | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 471.9 h*ng/mL | Geometric Coefficient of Variation 27.46 |
| Treatment E | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 8403 h*ng/mL | Geometric Coefficient of Variation 27.9 |
| Treatment F | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 8015 h*ng/mL | Geometric Coefficient of Variation 31.65 |
| Treatment F | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 486.9 h*ng/mL | Geometric Coefficient of Variation 26.47 |
| Treatment G | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 7727 h*ng/mL | Geometric Coefficient of Variation 30.82 |
| Treatment G | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 504.4 h*ng/mL | Geometric Coefficient of Variation 27.22 |
| Treatment H | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Dapagliflozin | 516.6 h*ng/mL | Geometric Coefficient of Variation 27.15 |
| Treatment H | Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | Metformin | 7578 h*ng/mL | Geometric Coefficient of Variation 35.76 |
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.93, 0.99]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.96, 1.01]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.94, 1]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.95, 1]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.96, 1.06]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.93, 1.07]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.99, 1.11]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.96, 1.1]
Primary
AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State.
To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 5307 h*ng/mL | Geometric Coefficient of Variation 26.54 |
| Treatment A | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 228.1 h*ng/mL | Geometric Coefficient of Variation 20.43 |
| Treatment B | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 239.1 h*ng/mL | Geometric Coefficient of Variation 21.1 |
| Treatment B | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 5205 h*ng/mL | Geometric Coefficient of Variation 28.59 |
| Treatment C | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 4211 h*ng/mL | Geometric Coefficient of Variation 28.71 |
| Treatment C | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 243.4 h*ng/mL | Geometric Coefficient of Variation 20.93 |
| Treatment D | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 248.8 h*ng/mL | Geometric Coefficient of Variation 17.92 |
| Treatment D | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 4212 h*ng/mL | Geometric Coefficient of Variation 27.22 |
| Treatment E | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 8040 h*ng/mL | Geometric Coefficient of Variation 27.82 |
| Treatment E | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 454.7 h*ng/mL | Geometric Coefficient of Variation 27.15 |
| Treatment F | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 472.1 h*ng/mL | Geometric Coefficient of Variation 26.72 |
| Treatment F | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 7798 h*ng/mL | Geometric Coefficient of Variation 32.77 |
| Treatment G | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 490.9 h*ng/mL | Geometric Coefficient of Variation 27.3 |
| Treatment G | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 7456 h*ng/mL | Geometric Coefficient of Variation 30.57 |
| Treatment H | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Dapagliflozin | 505.1 h*ng/mL | Geometric Coefficient of Variation 26.8 |
| Treatment H | AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | Metformin | 7401 h*ng/mL | Geometric Coefficient of Variation 34.75 |
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.94, 0.99]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.97, 1.02]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.93, 0.98]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.95, 1]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.97, 1.08]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.95, 1.06]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.97, 1.09]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.95, 1.07]
Primary
Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State
To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 510.2 ng/mL | Geometric Coefficient of Variation 22.23 |
| Treatment A | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 39.69 ng/mL | Geometric Coefficient of Variation 26.42 |
| Treatment B | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 503.4 ng/mL | Geometric Coefficient of Variation 22.16 |
| Treatment B | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 41.33 ng/mL | Geometric Coefficient of Variation 18.49 |
| Treatment C | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 65.28 ng/mL | Geometric Coefficient of Variation 25.49 |
| Treatment C | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 563.2 ng/mL | Geometric Coefficient of Variation 30.27 |
| Treatment D | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 573.9 ng/mL | Geometric Coefficient of Variation 28.55 |
| Treatment D | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 67.41 ng/mL | Geometric Coefficient of Variation 24.95 |
| Treatment E | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 87.48 ng/mL | Geometric Coefficient of Variation 30.14 |
| Treatment E | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 982.6 ng/mL | Geometric Coefficient of Variation 28.11 |
| Treatment F | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 90.14 ng/mL | Geometric Coefficient of Variation 32.09 |
| Treatment F | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 975.5 ng/mL | Geometric Coefficient of Variation 27.89 |
| Treatment G | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 125.6 ng/mL | Geometric Coefficient of Variation 30.77 |
| Treatment G | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 1016 ng/mL | Geometric Coefficient of Variation 35.36 |
| Treatment H | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Metformin | 998.5 ng/mL | Geometric Coefficient of Variation 36.05 |
| Treatment H | Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | Dapagliflozin | 132.7 ng/mL | Geometric Coefficient of Variation 28.31 |
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.93, 1.03]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.9, 1.06]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.89, 1.05]
Comparison: Dapagliflozin: Statistical Assessment of Bioequivalence for Dapagliflozin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.87, 1.03]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment A and B.90% CI: [0.96, 1.07]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 5/500 mg for Treatment C and D.90% CI: [0.92, 1.04]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment E and F.90% CI: [0.95, 1.06]
Comparison: Metformin: Statistical Assessment of Bioequivalence for Metformin following administration Dapagliflozin/Metformin XR 10/1000 mg for Treatment G and H.90% CI: [0.94, 1.1]
Secondary
Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F]
To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 2030 L/h | Standard Deviation 1407 |
| Treatment A | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 421.3 L/h | Standard Deviation 194.2 |
| Treatment B | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 2133 L/h | Standard Deviation 1891 |
| Treatment B | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 424.4 L/h | Standard Deviation 217.3 |
| Treatment C | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 2104 L/h | Standard Deviation 1309 |
| Treatment C | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 412.7 L/h | Standard Deviation 220.5 |
| Treatment D | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 2803 L/h | Standard Deviation 2066 |
| Treatment D | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 454.6 L/h | Standard Deviation 202.6 |
| Treatment E | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 3357 L/h | Standard Deviation 2549 |
| Treatment E | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 476.5 L/h | Standard Deviation 224 |
| Treatment F | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 3324 L/h | Standard Deviation 2713 |
| Treatment F | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 433.3 L/h | Standard Deviation 196.1 |
| Treatment G | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 441.7 L/h | Standard Deviation 191.7 |
| Treatment G | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 3635 L/h | Standard Deviation 2648 |
| Treatment H | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Metformin | 3212 L/h | Standard Deviation 2079 |
| Treatment H | Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | Dapagliflozin | 421.4 L/h | Standard Deviation 163.1 |
Secondary
Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F]
To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 21.62 L | Standard Deviation 4.617 |
| Treatment A | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 93.78 L | Standard Deviation 22.71 |
| Treatment B | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 20.55 L | Standard Deviation 4.506 |
| Treatment B | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 94.89 L | Standard Deviation 26.81 |
| Treatment C | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 20.32 L | Standard Deviation 4.503 |
| Treatment C | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 118.1 L | Standard Deviation 32.16 |
| Treatment D | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 19.68 L | Standard Deviation 3.65 |
| Treatment D | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 116.9 L | Standard Deviation 36.62 |
| Treatment E | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 21.93 L | Standard Deviation 5.747 |
| Treatment E | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 123.5 L | Standard Deviation 34.68 |
| Treatment F | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 130.5 L | Standard Deviation 39.23 |
| Treatment F | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 21.22 L | Standard Deviation 5.585 |
| Treatment G | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 20.49 L | Standard Deviation 5.138 |
| Treatment G | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 134.9 L | Standard Deviation 37.59 |
| Treatment H | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Dapagliflozin | 20.00 L | Standard Deviation 4.974 |
| Treatment H | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | Metformin | 140 L | Standard Deviation 50.7 |
Secondary
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz]
To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 13.48 Hour (h) | Standard Deviation 7.873 |
| Treatment A | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 14.01 Hour (h) | Standard Deviation 6.747 |
| Treatment B | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 12.87 Hour (h) | Standard Deviation 6.587 |
| Treatment B | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 14.65 Hour (h) | Standard Deviation 7.245 |
| Treatment C | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 13.73 Hour (h) | Standard Deviation 6.203 |
| Treatment C | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 11.91 Hour (h) | Standard Deviation 7.351 |
| Treatment D | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 13.52 Hour (h) | Standard Deviation 8.76 |
| Treatment D | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 16.55 Hour (h) | Standard Deviation 8.26 |
| Treatment E | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 14.88 Hour (h) | Standard Deviation 6.272 |
| Treatment E | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 14.18 Hour (h) | Standard Deviation 7.718 |
| Treatment F | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 13.74 Hour (h) | Standard Deviation 6.984 |
| Treatment F | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 14.42 Hour (h) | Standard Deviation 5.778 |
| Treatment G | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 14.72 Hour (h) | Standard Deviation 5.641 |
| Treatment G | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 14.38 Hour (h) | Standard Deviation 8.241 |
| Treatment H | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Metformin | 15.94 Hour (h) | Standard Deviation 9.671 |
| Treatment H | Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | Dapagliflozin | 15.11 Hour (h) | Standard Deviation 5.998 |
Secondary
Time to Reach Maximum Plasma Concentration (t Max)
To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states.
Time frame: Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period
Population: PK Analysis Set: All subjects in the safety analysis set for whom at least one of the primary PK parameters could be calculated for at least one analyte (dapagliflozin or metformin), and who had no major protocol deviations thought to impact on analysis of the PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment A | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 6.00 Hour |
| Treatment A | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 2.50 Hour |
| Treatment B | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 3.00 Hour |
| Treatment B | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 6.00 Hour |
| Treatment C | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 1.00 Hour |
| Treatment C | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment D | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 1.00 Hour |
| Treatment D | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment E | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment E | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 2.00 Hour |
| Treatment F | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 2.00 Hour |
| Treatment F | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment G | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment G | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 1.00 Hour |
| Treatment H | Time to Reach Maximum Plasma Concentration (t Max) | Metformin | 4.00 Hour |
| Treatment H | Time to Reach Maximum Plasma Concentration (t Max) | Dapagliflozin | 1.00 Hour |