PK Study of Dapagliflozin in Pediatric Subjects With T2DM

Study Overview
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Brief Summary
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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
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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

Official Title
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A Randomized, Multi-Center, Parallel Group, Single-Dose, Pharmacokinetics and Pharmacodynamics Study of Dapagliflozin in Children and Adolescents Aged 10 to 17 Years With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Dapagliflozin
* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin 2.5 mg<br> | Drug: Dapagliflozin<br>* Tablet, Oral, 2.5 mg, Single-dose<br>|
| Experimental: Dapagliflozin 5 mg<br> | Drug: Dapagliflozin<br>* Tablet, Oral, 5 mg, Single-dose<br>|
| Experimental: Dapagliflozin 10 mg<br> | Drug: Dapagliflozin<br>* Tablet, Oral, 10 mg, Single-dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 
| 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). | 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 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). | 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 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). | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 
| 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. | 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 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). | 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 (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) | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 
| 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). | 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 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). | 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 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). | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 
| 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. | 11 time points: Immediately pre-dose, 0.5, 0.75, 1.0, 1.5, 4, 8, 12, 14, 24, and 48 hours post-dose | 
| 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). | Day 1 (Pre-dose) to Day 2 | 
| 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). | Day 1 (Pre-dose) to Day 2 | 
| 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 of dose to 24 hours post-dose, Day 1 to Day 2 | 
| 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. | Day 1 to Day 3 | 
| 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. | Day 1 (Pre-dose) to Day 3 | 
| 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). | Day 1 (Pre-dose) to Day 3 | 
| 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) | Day 1 (Pre-dose) to Day 3 | 
| 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). | Day 1 (Pre-dose) to Day 3 |