Type 2 Diabetes Mellitus
Conditions
Brief summary
The primary purpose of this study is to evaluate the pharmacokinetics (PK) of Dapagliflozin in pediatric subjects with type 2 diabetes mellitus (T2DM)
Detailed description
Primary purpose: The primary purpose is to assess the pharmacokinetics of a single dose of Dapagliflozin in the range of 2.5 to 10 mg in pediatric subjects aged 10 to 17 years with T2DM
Interventions
DRUGDapagliflozin
Tablet, Oral, 2.5 mg, Single-dose
Sponsors
Bristol-Myers Squibb
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of T2DM * Male and female subjects ages 10-17 * Glycosylated Hemoglobin A1c (HbA1c) ≥6 to 10% * Body weight ≥30 kg
Exclusion criteria
* Fasting plasma glucose (FPG) \>240 mg/dL at screening * Abnormal renal function * Active liver disease and/or significant abnormal liver function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanograms per milliliter (ng/mL). |
| Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Time of maximum observed plasma concentration (Tmax) for Dapagliflozin was derived from plasma concentrations versus time data. Medians were reported in hours (h). |
| Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Area under the plasma concentration-time curve from time zero extrapolated to infinite time was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng\*hr/mL). |
| Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanogram hours per milliliter (ng\*h/mL). |
| Mean Plasma Half-life (T-HALF) of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentrations versus time data. Means are reported in hours. |
| Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Apparent clearance after extravascular administration (CL/F) of Dapagliflozin was derived from plasma concentrations versus time data. Geometric means are reported in milliliters per minute (mL/min). |
| Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Geometric mean of apparent volume of distribution at terminal phase after extravascular administration of Dapagliflozin was derived from plasma concentration versus time data. Geometric means are reported in Liters (L) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Fasting Plasma Glucose From Baseline Until Day 2 | Day 1 (Pre-dose) to Day 2 | Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Mean change from baseline to Day 2 is reported in milligrams per deciliter (mg/dL). |
| Mean Total Amount of Glucose Excreted in Urine Over 24 Hours | Time of dose to 24 hours post-dose, Day 1 to Day 2 | The total amount of glucose excreted in urine was measured for 24 hours following administration of Dapagliflozin. Means are reported in grams. |
| Number of Participants With Marked Hematology Laboratory Abnormalities | Day 1 (Pre-dose) to Day 3 | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose (Day -1). Lab values that met the following criteria were marked as abnormalities: Hemoglobin (grams per deciliter:g/dL): \<0.85\*Pre-Rx. Hematocrit (%): \<0.85\*Pre-Rx. Platelet Count (x10\^9 cells per liter:c/L): \<0.85\*LLN or \>1.5\*ULN (if Pre-Rx\<LLN, use \<0.85\*Pre-Rx). Leukocytes (x10\^3 cells per microliter: c/uL): \<0.9\*LLN, \>1.2\*ULN (if Pre-Rx\<LLN, use \<0.85\*Pre-Rx or \>ULN, if Pre- Rx\>ULN, use \>1.15\*Pre-Rx or \<LLN). Neutrophils (Absolute) (x10\^3 c/uL): \<=1.5. Lymphocytes (Absolute) (x10\^3 c/uL): \<0.75 or \>7.5. Monocytes (Absolute) (x10\^3 c/uL): \>2.000. Basophils (x10\^3 c/uL): \>0.4. Eosinophils (Absolute) (x10\^3 c/uL): \>0.75. Blasts (Absolute) (x10\^9 c/L) \> 0. |
| Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Day 1 to Day 3 | Participants were followed from dosing on Day 1 until study discharge on Day 3. The number of participants with investigator-assessed clinically-important abnormalities in vital sign measurements, ECGs or physical examinations was reported. |
| Number of Participants With Marked Abnormalities in Other Chemistry Testing | Day 1 (Pre-dose) to Day 3 | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Glucose, fasting serum (mmol/L): \<0.8\*LLN, \>1.3\*ULN (if Pre-Rx\<LLN: \<0.8\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>2.0\*Pre-Rx, \<LLN). Protein (grams per deciliter: g/L): \<0.9\*LLN, \>1.1\*ULN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.1\*Pre-Rx, \<LLN). Albumin (g/L): \<0.9\*LLN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx). Uric Acid (mmol/L): \>1.2\*ULN (if Pre-Rx\>ULN: \>1.25\*Pre-Rx). Lactate Dehydrogenase (U/L): \>1.25\*ULN (if Pre-Rx\>ULN: \>1.5\*Pre-Rx) |
| Number of Participants With Marked Urinalysis Abnormalities | Day 1 (Pre-dose) to Day 3 | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Blood, urine (Qualitative): \>=2 (If Pre-Rx \>= 1, \>=2\*Pre-Rx). Glucose, urine (Qualitative): \>=1, (If Pre-Rx \>=1, \>=2\*Pre-Rx). Protein, urine (Qualitative): \>=2 (If Pre-Rx \>=1, \>=2\*Pre-Rx). Red Blood Cells (RBC), urine (RBC per High Power Field (hpf)): \>=2 (If Pre-Rx\>=2, \>=4). White Blood Cells (WBC), urine (hpf): \>=2 (If Pre-Rx\>=2, \>=4). |
| Number of Participants With Marked Serum Chemistry Abnormalities | Day 1 (Pre-dose) to Day 3 | LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Alkaline Phosphatase (units per liter: U/L), Aspartate Aminotransferase (U/L), Alanine Aminotransferase (U/L): \>1.25\*ULN (if Pre-Rx\>ULN, use \>1.25\*Pre-Rx). Bilirubin (milligrams per deciliter: mg/dL): \>1.1\*ULN (if Pre-Rx\>ULN, use \>1.25\*Pre-Rx). Blood Urea Nitrogen (mg/dL): \>1.1\*ULN (if Pre-Rx\>ULN, use \>1.2\*Pre-Rx). Creatinine (micromoles per Liter (umol/L)): \>1.5\*ULN if Pre-Rx missing or \<= ULN, \>1.33\*Pre-Rx if PreRx \> ULN. Sodium (mmol/L): \>1.05\*ULN, 1.05\*Pre-Rx if Pre-Rx\>ULN: \<0.95\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.05\*Pre-Rx, \<LLN). Potassium(mmol/L), Chloride (mmol/L), Calcium(mmol/L): \<0.9\*LLN, \>1.1\*ULN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.1\*Pre-Rx, \<LLN). Phosphorus (mg/dL): \<0.85\*LLN, \>1.25\*ULN (if Pre-Rx\<LLN, \<0.85\*Pre-Rx, \>ULN. if Pre-Rx\>ULN: \>1.25\*Pre-Rx, \<LLN). |
| Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanograms per milliliter (ng/mL). |
| Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Time of maximum observed plasma concentration (Tmax) for Dapagliflozin 3-O-Glucuronide was derived from plasma concentrations versus time data. Medians were reported in hours (h). |
| Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin 3-O-Glucuronide | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Area under the plasma concentration-time curve from time zero extrapolated to infinite time was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng\*hr/mL). |
| Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin 3-O-Glucuronide | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanogram hours per milliliter (ng\*h/mL). |
| Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentration versus time data. Means are reported in hours. |
| Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 1 (Pre-dose) to Day 2 | Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Means are reported in milligrams per deciliter (mg/dL). |
Countries
Mexico, United States
Participant flow
Pre-assignment details
53 participants enrolled; 24 randomized; 24 treated with study drug. 29 participants were not randomized due to no longer meeting study criteria (25), withdrawal of consent (2), or other reasons (2).
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 2.5 mg Dapagliflozin: Tablet, Oral, 2.5 mg, Single-dose | 8 |
| Dapagliflozin 5 mg Dapagliflozin: Tablet, Oral, 5 mg, Single-dose | 8 |
| Dapagliflozin 10 mg Dapagliflozin: Tablet, Oral, 10 mg, Single-dose | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Dapagliflozin 2.5 mg | Dapagliflozin 5 mg | Dapagliflozin 10 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 15.0 years STANDARD_DEVIATION 1.69 | 14.0 years STANDARD_DEVIATION 2.39 | 14.6 years STANDARD_DEVIATION 2.13 | 14.5 years STANDARD_DEVIATION 2.04 |
| Age, Customized 10 to <= 15 years | 5 participants | 5 participants | 4 participants | 14 participants |
| Age, Customized 16 to <= 17 years | 3 participants | 3 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 8 | 0 / 8 | 3 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin
Apparent clearance after extravascular administration (CL/F) of Dapagliflozin was derived from plasma concentrations versus time data. Geometric means are reported in milliliters per minute (mL/min).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin | 413 mL/min | Geometric Coefficient of Variation 26 |
| Dapagliflozin 5 mg | Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin | 418 mL/min | Geometric Coefficient of Variation 27 |
| Dapagliflozin 10 mg | Geometric Mean of Apparent Clearance After Extravascular Administration (CL/F) of Dapagliflozin | 391 mL/min | Geometric Coefficient of Variation 25 |
Primary
Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin
Geometric mean of apparent volume of distribution at terminal phase after extravascular administration of Dapagliflozin was derived from plasma concentration versus time data. Geometric means are reported in Liters (L)
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin | 468 Liters | Geometric Coefficient of Variation 34 |
| Dapagliflozin 5 mg | Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin | 343 Liters | Geometric Coefficient of Variation 45 |
| Dapagliflozin 10 mg | Geometric Mean of Apparent Volume of Distribution at Terminal Phase After Extravascular Administration (Vz/F) of Dapagliflozin | 355 Liters | Geometric Coefficient of Variation 34 |
Primary
Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin
Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanogram hours per milliliter (ng\*h/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin | 92.3 ng*h/mL | Geometric Coefficient of Variation 27 |
| Dapagliflozin 5 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin | 189 ng*h/mL | Geometric Coefficient of Variation 31 |
| Dapagliflozin 10 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin | 418 ng*h/mL | Geometric Coefficient of Variation 31 |
Primary
Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin
Area under the plasma concentration-time curve from time zero extrapolated to infinite time was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng\*hr/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin | 101 ng*h/mL | Geometric Coefficient of Variation 23 |
| Dapagliflozin 5 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin | 199 ng*h/mL | Geometric Coefficient of Variation 29 |
| Dapagliflozin 10 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin | 427 ng*h/mL | Geometric Coefficient of Variation 31 |
Primary
Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin
Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin over time. The geometric means are reported in nanograms per milliliter (ng/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable pharmacokinetic (PK) profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin | 24.8 ng/mL | Geometric Coefficient of Variation 34 |
| Dapagliflozin 5 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin | 48.4 ng/mL | Geometric Coefficient of Variation 41 |
| Dapagliflozin 10 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin | 118 ng/mL | Geometric Coefficient of Variation 35 |
Primary
Mean Plasma Half-life (T-HALF) of Dapagliflozin
Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentrations versus time data. Means are reported in hours.
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin | 14.1 hours | Standard Deviation 5.59 |
| Dapagliflozin 5 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin | 10.3 hours | Standard Deviation 3.72 |
| Dapagliflozin 10 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin | 10.7 hours | Standard Deviation 2.16 |
Primary
Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin
Time of maximum observed plasma concentration (Tmax) for Dapagliflozin was derived from plasma concentrations versus time data. Medians were reported in hours (h).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapagliflozin 2.5 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin | 1.50 hours |
| Dapagliflozin 5 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin | 0.960 hours |
| Dapagliflozin 10 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin | 0.875 hours |
Secondary
Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin 3-O-Glucuronide
Area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-T)) was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanogram hours per milliliter (ng\*h/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin 3-O-Glucuronide | 95.8 ng*h/mL | Geometric Coefficient of Variation 20 |
| Dapagliflozin 5 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin 3-O-Glucuronide | 208 ng*h/mL | Geometric Coefficient of Variation 32 |
| Dapagliflozin 10 mg | Geometric Mean of Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Dapagliflozin 3-O-Glucuronide | 612 ng*h/mL | Geometric Coefficient of Variation 24 |
Secondary
Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin 3-O-Glucuronide
Area under the plasma concentration-time curve from time zero extrapolated to infinite time was derived from concentration versus time data. Geometric means are reported in nanogram hours per milliliter (ng\*hr/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin 3-O-Glucuronide | 105 ng*hr/mL | Geometric Coefficient of Variation 23 |
| Dapagliflozin 5 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin 3-O-Glucuronide | 232 ng*hr/mL | Geometric Coefficient of Variation 30 |
| Dapagliflozin 10 mg | Geometric Mean of Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Dapagliflozin 3-O-Glucuronide | 658 ng*hr/mL | Geometric Coefficient of Variation 21 |
Secondary
Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide
Maximum observed plasma concentration (Cmax) was measured by plasma concentration of Dapagliflozin 3-O-Glucuronide over time. The geometric means are reported in nanograms per milliliter (ng/mL).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide | 24.6 ng/mL | Geometric Coefficient of Variation 45 |
| Dapagliflozin 5 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide | 49.0 ng/mL | Geometric Coefficient of Variation 50 |
| Dapagliflozin 10 mg | Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin 3-O-Glucuronide | 154 ng/mL | Geometric Coefficient of Variation 27 |
Secondary
Mean Change in Fasting Plasma Glucose From Baseline Until Day 2
Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Mean change from baseline to Day 2 is reported in milligrams per deciliter (mg/dL).
Time frame: Day 1 (Pre-dose) to Day 2
Population: All treated participants with evaluable PD profiles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Mean Change in Fasting Plasma Glucose From Baseline Until Day 2 | -46.7 mg/dL | Standard Deviation 60.08 |
| Dapagliflozin 5 mg | Mean Change in Fasting Plasma Glucose From Baseline Until Day 2 | -32.8 mg/dL | Standard Deviation 42.41 |
| Dapagliflozin 10 mg | Mean Change in Fasting Plasma Glucose From Baseline Until Day 2 | -22.0 mg/dL | Standard Deviation 27.32 |
Secondary
Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting
Plasma glucose concentrations were evaluated in all treated subjects at Day 1 pre-dose and at Day 2 after fasting for 8 hours. Means are reported in milligrams per deciliter (mg/dL).
Time frame: Day 1 (Pre-dose) to Day 2
Population: All treated participants with evaluable pharmacodynamic (PD) profiles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dapagliflozin 2.5 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 1 Pre-dose (n= 6, 8, 8) | 146.2 mg/dL | Standard Deviation 72.56 |
| Dapagliflozin 2.5 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 2 after 8 hour fast (n= 3, 8, 7) | 124.0 mg/dL | Standard Deviation 45.21 |
| Dapagliflozin 5 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 1 Pre-dose (n= 6, 8, 8) | 152.1 mg/dL | Standard Deviation 49.06 |
| Dapagliflozin 5 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 2 after 8 hour fast (n= 3, 8, 7) | 119.4 mg/dL | Standard Deviation 17.18 |
| Dapagliflozin 10 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 1 Pre-dose (n= 6, 8, 8) | 139.8 mg/dL | Standard Deviation 39.63 |
| Dapagliflozin 10 mg | Mean Fasting Plasma Glucose Concentrations at Pre-dose on Day 1 and on Day 2 After an 8-hr Fasting | Day 2 after 8 hour fast (n= 3, 8, 7) | 119.0 mg/dL | Standard Deviation 29.15 |
Secondary
Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide
Plasma half-life (T-Half) for Dapagliflozin was derived from plasma concentration versus time data. Means are reported in hours.
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide | 4.62 hours | Standard Deviation 3.086 |
| Dapagliflozin 5 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide | 8.71 hours | Standard Deviation 2.024 |
| Dapagliflozin 10 mg | Mean Plasma Half-life (T-HALF) of Dapagliflozin 3-O-Glucuronide | 8.37 hours | Standard Deviation 3.33 |
Secondary
Mean Total Amount of Glucose Excreted in Urine Over 24 Hours
The total amount of glucose excreted in urine was measured for 24 hours following administration of Dapagliflozin. Means are reported in grams.
Time frame: Time of dose to 24 hours post-dose, Day 1 to Day 2
Population: All treated participants with evaluable PD profiles
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Mean Total Amount of Glucose Excreted in Urine Over 24 Hours | 52.84 grams | Standard Deviation 27.18 |
| Dapagliflozin 5 mg | Mean Total Amount of Glucose Excreted in Urine Over 24 Hours | 62.39 grams | Standard Deviation 26.55 |
| Dapagliflozin 10 mg | Mean Total Amount of Glucose Excreted in Urine Over 24 Hours | 89.04 grams | Standard Deviation 41.25 |
Secondary
Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide
Time of maximum observed plasma concentration (Tmax) for Dapagliflozin 3-O-Glucuronide was derived from plasma concentrations versus time data. Medians were reported in hours (h).
Time frame: 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose
Population: All treated participants with evaluable PK profiles
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapagliflozin 2.5 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide | 1.50 hours |
| Dapagliflozin 5 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide | 1.50 hours |
| Dapagliflozin 10 mg | Median Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin 3-O-Glucuronide | 1.50 hours |
Secondary
Number of Participants With Marked Abnormalities in Other Chemistry Testing
LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Glucose, fasting serum (mmol/L): \<0.8\*LLN, \>1.3\*ULN (if Pre-Rx\<LLN: \<0.8\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>2.0\*Pre-Rx, \<LLN). Protein (grams per deciliter: g/L): \<0.9\*LLN, \>1.1\*ULN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.1\*Pre-Rx, \<LLN). Albumin (g/L): \<0.9\*LLN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx). Uric Acid (mmol/L): \>1.2\*ULN (if Pre-Rx\>ULN: \>1.25\*Pre-Rx). Lactate Dehydrogenase (U/L): \>1.25\*ULN (if Pre-Rx\>ULN: \>1.5\*Pre-Rx)
Time frame: Day 1 (Pre-dose) to Day 3
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Glucose, fasting serum, high (n=7, 7, 7) | 1 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Additional other chemistry marked abnormalities | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Glucose, fasting serum, high (n=7, 7, 7) | 1 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Additional other chemistry marked abnormalities | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Glucose, fasting serum, high (n=7, 7, 7) | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Abnormalities in Other Chemistry Testing | Additional other chemistry marked abnormalities | 0 participants |
Secondary
Number of Participants With Marked Hematology Laboratory Abnormalities
LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose (Day -1). Lab values that met the following criteria were marked as abnormalities: Hemoglobin (grams per deciliter:g/dL): \<0.85\*Pre-Rx. Hematocrit (%): \<0.85\*Pre-Rx. Platelet Count (x10\^9 cells per liter:c/L): \<0.85\*LLN or \>1.5\*ULN (if Pre-Rx\<LLN, use \<0.85\*Pre-Rx). Leukocytes (x10\^3 cells per microliter: c/uL): \<0.9\*LLN, \>1.2\*ULN (if Pre-Rx\<LLN, use \<0.85\*Pre-Rx or \>ULN, if Pre- Rx\>ULN, use \>1.15\*Pre-Rx or \<LLN). Neutrophils (Absolute) (x10\^3 c/uL): \<=1.5. Lymphocytes (Absolute) (x10\^3 c/uL): \<0.75 or \>7.5. Monocytes (Absolute) (x10\^3 c/uL): \>2.000. Basophils (x10\^3 c/uL): \>0.4. Eosinophils (Absolute) (x10\^3 c/uL): \>0.75. Blasts (Absolute) (x10\^9 c/L) \> 0.
Time frame: Day 1 (Pre-dose) to Day 3
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Leukocytes, low (n=8, 8, 8) | 1 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Neutrophils, low (n=8, 8, 8) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Leukocytes, low (n=8, 8, 8) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Neutrophils, low (n=8, 8, 8) | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Leukocytes, low (n=8, 8, 8) | 1 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Hematology Laboratory Abnormalities | Neutrophils, low (n=8, 8, 8) | 1 participants |
Secondary
Number of Participants With Marked Serum Chemistry Abnormalities
LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Alkaline Phosphatase (units per liter: U/L), Aspartate Aminotransferase (U/L), Alanine Aminotransferase (U/L): \>1.25\*ULN (if Pre-Rx\>ULN, use \>1.25\*Pre-Rx). Bilirubin (milligrams per deciliter: mg/dL): \>1.1\*ULN (if Pre-Rx\>ULN, use \>1.25\*Pre-Rx). Blood Urea Nitrogen (mg/dL): \>1.1\*ULN (if Pre-Rx\>ULN, use \>1.2\*Pre-Rx). Creatinine (micromoles per Liter (umol/L)): \>1.5\*ULN if Pre-Rx missing or \<= ULN, \>1.33\*Pre-Rx if PreRx \> ULN. Sodium (mmol/L): \>1.05\*ULN, 1.05\*Pre-Rx if Pre-Rx\>ULN: \<0.95\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.05\*Pre-Rx, \<LLN). Potassium(mmol/L), Chloride (mmol/L), Calcium(mmol/L): \<0.9\*LLN, \>1.1\*ULN (if Pre-Rx\<LLN: \<0.9\*Pre-Rx, \>ULN. If Pre-Rx\>ULN: \>1.1\*Pre-Rx, \<LLN). Phosphorus (mg/dL): \<0.85\*LLN, \>1.25\*ULN (if Pre-Rx\<LLN, \<0.85\*Pre-Rx, \>ULN. if Pre-Rx\>ULN: \>1.25\*Pre-Rx, \<LLN).
Time frame: Day 1 (Pre-dose) to Day 3
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Number of Participants With Marked Serum Chemistry Abnormalities | ALT, high (8, 8, 8) | 1 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Serum Chemistry Abnormalities | AST, high (n=8, 8, 8) | 1 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Serum Chemistry Abnormalities | ALT, high (8, 8, 8) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Serum Chemistry Abnormalities | AST, high (n=8, 8, 8) | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Serum Chemistry Abnormalities | ALT, high (8, 8, 8) | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Serum Chemistry Abnormalities | AST, high (n=8, 8, 8) | 0 participants |
Secondary
Number of Participants With Marked Urinalysis Abnormalities
LLN=Lower Limit of Normal, ULN=Upper Limit of Normal, Pre-Rx=Value before first dose. Lab values that met the following criteria were marked as abnormalities: Blood, urine (Qualitative): \>=2 (If Pre-Rx \>= 1, \>=2\*Pre-Rx). Glucose, urine (Qualitative): \>=1, (If Pre-Rx \>=1, \>=2\*Pre-Rx). Protein, urine (Qualitative): \>=2 (If Pre-Rx \>=1, \>=2\*Pre-Rx). Red Blood Cells (RBC), urine (RBC per High Power Field (hpf)): \>=2 (If Pre-Rx\>=2, \>=4). White Blood Cells (WBC), urine (hpf): \>=2 (If Pre-Rx\>=2, \>=4).
Time frame: Day 1 (Pre-dose) to Day 3
Population: All treated participants with evaluable lab results
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Number of Participants With Marked Urinalysis Abnormalities | WBC, urine, high (n=4, 2, 3) | 1 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Urinalysis Abnormalities | Protein, urine, high (n=8, 8, 8) | 0 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Urinalysis Abnormalities | Glucose, urine, high (n=8, 8, 8) | 2 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Urinalysis Abnormalities | RBC, urine, high (n=1, 1, 4) | 0 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Marked Urinalysis Abnormalities | Blood, urine, high (n=8, 8, 8) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Urinalysis Abnormalities | RBC, urine, high (n=1, 1, 4) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Urinalysis Abnormalities | WBC, urine, high (n=4, 2, 3) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Urinalysis Abnormalities | Blood, urine, high (n=8, 8, 8) | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Urinalysis Abnormalities | Glucose, urine, high (n=8, 8, 8) | 3 participants |
| Dapagliflozin 5 mg | Number of Participants With Marked Urinalysis Abnormalities | Protein, urine, high (n=8, 8, 8) | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Abnormalities | Blood, urine, high (n=8, 8, 8) | 2 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Abnormalities | WBC, urine, high (n=4, 2, 3) | 1 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Abnormalities | Protein, urine, high (n=8, 8, 8) | 3 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Abnormalities | RBC, urine, high (n=1, 1, 4) | 3 participants |
| Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Abnormalities | Glucose, urine, high (n=8, 8, 8) | 4 participants |
Secondary
Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration.
Participants were followed from dosing on Day 1 until study discharge on Day 3. The number of participants with investigator-assessed clinically-important abnormalities in vital sign measurements, ECGs or physical examinations was reported.
Time frame: Day 1 to Day 3
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dapagliflozin 2.5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Vital sign abnormalities | 0 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Physical examination abnormalities | 0 participants |
| Dapagliflozin 2.5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | ECG abnormalities | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | ECG abnormalities | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Physical examination abnormalities | 0 participants |
| Dapagliflozin 5 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Vital sign abnormalities | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | ECG abnormalities | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Physical examination abnormalities | 0 participants |
| Dapagliflozin 10 mg | Number of Participants With Vital Sign Abnormalities, Electrocardiogram (ECG) Abnormalities, or Physical Examination Abnormalities Following Study Drug Administration. | Vital sign abnormalities | 0 participants |