Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to evaluate whether the pharmacokinetics (body concentrations/metabolism of the drug) of Saxagliptin and Dapagliflozin are affected when they are administered together
Interventions
DRUGSaxagliptin
DRUGDapagliflozin
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy subjects as determined by no clinically significant deviation from normal in medical history, Physical Examination, vital signs, 12-lead ECG, and clinical laboratory determinations * Body mass index (BMI) of 18 to 30 kg/m2 * Men and women, ages 18 to 45 years * Women of childbearing potential must use acceptable methods of highly effective birth control
Exclusion criteria
* History of chronic or recurrent urinary tract infection for females * History of allergies or adverse reactions to Dipeptidyl peptidase-IV (DPP4) or Sodium-glucose transporter type 2 (SGLT2) inhibitors * Any significant acute or chronic medical illness * Current or recent gastrointestinal disease * Any major surgery within 4 weeks of study drug administration * Prior exposure to saxagliptin or dapagliflozin or related drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin From a Single Dose of Dapagliflozin Versus Cmax of Dapagliflozin From Co-administered Saxagliptin Plus Dapagliflozin - Pharmacokinetic Evaluable Population | Day 1 (0 h to 60 h post dose) in each period | The geometric mean of the maximum observed plasma concentration (Cmax) is presented below; serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h,and 60 h postdose, relative to dosing on Day 1 in each cross over period and these data are summarized in the Pharmacokinetic (PK) parameter of Cmax presented here. Plasma samples were analyzed for dapagliflozin by High Performance Liquid chromatography-Mass Spectrometry (HPLC-MS/MS) using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Dapagliflozin Cmax was derived from plasma concentration versus time data using a non-compartmental method, using a validated PK analysis program ™. Actual sampling times were used for PK calculations. Cmax was reported in ng/mL. |
| Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity [AUC(INF)] of Dapagliflozin From a Single Dose of Dapagliflozin Versus AUC (INF) of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | AUC(INF) is area under the plasma concentration-time curve from time 0 extrapolated to infinity. Serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(INF) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL). |
| Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus AUC(0-T) for Dapagliflozin When Co-administered With 5 mg Saxagliptin | Day 1 (0h to 60h post dose) in each period | AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method). Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(0-T) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL). |
| Maximum Observed Concentration (Cmax) of a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography-Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). Cmax for Saxagliptin was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in nanograms per milliliter (ng/mL). |
| AUC(0-T) of Saxagliptin From Single Dose 5 mg Saxagliptin Versus AUC(0-T) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography-Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(0-T), the area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL). |
| AUC(INF) of Saxagliptin From a Single Dose of 5 mg Saxagliptin Versus AUC(INF) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of the Saxagliptin Total Active Moiety From a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Cmax of saxagliptin total active moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin) was derived from the plasma concentration versus time profile for the saxagliptin total active moiety. Measurement was in nano Molars (nM). |
| AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. AUC(INF) is area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) and both were derived from the plasma concentration versus time profile using a validated PK analysis program ™. Total moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin), AUC(0-T)and AUC(INF) were measured in nano Molars\*hours (nM\*h). |
| Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin and 5-OH by LC-MS/MS using a validated method. Tmax was derived from the plasma concentration versus time profile for study drug and was measured in hours (h). Saxagliptin was the drug, 5-OH saxagliptin was the metabolite, and Saxagliptin total Active Moiety was molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin. |
| Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours (h). |
| Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Saxagliptin is the parent drug and 5-OH saxagliptin is the metabolite. The molecular weights to be used for the molar ratios were 315.42 and 331.42 for saxagliptin and 5-OH, respectively. Plasma samples were analyzed for saxagliptin and for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL and 0.200 ng/mL to 100.0 ng/mL for saxagliptin and 5-OH, respectively). |
| Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Day 1 to end of study (16 days) | Adverse event (AE)=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE)=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. End of study was approximately 16 days and was the time for a participant to conclude each of the 3 periods (including the 6 day washout between periods). |
| Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Baseline to Day 1 of each period | Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal (LLN); upper limit of normal (ULN); pretreatment(pre-RX); treatment (RX). Hemoglobin (g/L): \<0.85\* pre-RX; hematocrit (vol): \<0.85\*pre-RX; erythrocytes (\*10\^12 c/L): \<0.85\*pre-RX; platelet count (\*10\^9 c/L): \<0.85\*LLN if pre-RX\>=LLN, or if Pre-Tx \<LLN; leukocytes (\*10\^9 c/L): \<0.85\*LLN if pre-RX \<LLN,or \<0.9\*LLN if LLN\<=Pre-RX\<=ULN; neutrophils+bands (\*10\^9 c/L): \<0.85\*Pre-RX if Pre-RX \<1.5 or \<1.5 if Pre-RX \>=1.5; eosinophils (\*10\^9 c/L): if value \>0.75; basophils (\*10\^9 c/L): if value \>0.4; monocytes (\*10\^9c/L): if value \>2; lymphocytes (\*10\^9 c/L): if value \<0.750 or if value \>7.50. |
| Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus Tmax of Dapagliflozin When Co-administered With 5 mg Saxagliptin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. Tmax was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours. |
| Mean Change From Baseline in Heart Rate - Safety Population | Baseline to Day 1 in each period | Heart rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in beats per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. |
| Mean Change From Baseline in Respiration Rate - Safety Population | Baseline to Day 1 in each period | Respiration rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in breaths per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. |
| Mean Change From Baseline in Temperature - Safety Population | Baseline to Day 1 in each period | Participant had their temperature taken after quietly sitting for at least 5 minutes and it was measured as degrees of centigrade (C). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. |
| Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Baseline to Day 1 in each period | Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal(LLN); upper limit of normal (ULN); pre-treatment(Pre-Rx). Alkaline phosphatase U/L:\>1.25\*Pre-RX if Pre-Rx \>ULN or \>1.25\*ULN if Pre-Rx \<=ULN; aspartate aminotransferase (AST) U/L: \>1.25\*Pre-Rx if Pre-Rx \> ULN or 1.25\*ULN if Pre-Rx \<= ULN;alanine aminotransferase (ALT) U/L: \>1.25\*Pre-Rx if Pre-Rx\>ULN or 1.25\*ULN if Pre-Rx\<=ULN;blood urea nitrogen (BUN)mmol/L: \>1.1\*ULN if Pre-Rx \<=ULN or \>1.2\*Pre-Rx if Pre-Rx \>ULN; total bilirubin µmol/L: \>1.1\*ULN if Pre-Rx \<=ULN or \>1.25\*Pre-Rx if Pre-Rx \>ULN;direct bilirubin µmol/L: \>1.1\*ULN if Pre-Rx \<= ULN or \>1.25\*Pre-Rx if Pre-Rx \> ULN; creatine phosphokinase (CK) U/L: \>1.5\*Pre-Rx if Pre-Rx \>ULN or \>1.5\*ULN if Pre-Rx \<= ULN. |
| Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Baseline to Day 1 of each period | Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Fasted for 10 hours prior to samples taken. LLN=lower limit of normal; ULN=upper limit of normal; pretreatment (Pre-Rx). Normals: Urine glucose qualitative: dipstick \>=1 if Pre-Rx \<1 or 2\*Pre-Rx if Pre-Rx\>=1; urine microscopic white blood cell count (WBC): \>=2 if Pre-Rx \<2 or \>=4 if Pre-Rx \>=2;urine red blood cell count (RBC):\>=2 if Pre-Rx \<2 or \>=4 if Pre-Rx \>=2. |
| Number of Participants With Change From Baseline in ECG Interval - Safety Population | Baseline to end of study (16 days) | A 12-Lead electrocardiogram (ECG) was performed and recorded after the participant had been supine for at least 5 minutes. ECGs done at baseline (Day-1 of Period 1) and at end of study; therefore the results are presented by sequence, and cannot be presented by treatment. QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec). Abnormality criteria: QT/QTcF QT or QTcF \>450 msec and \<=480 msec at any postdose time point and not present at baseline. QT or QTcF \>480 msec and \<=500 msec at any postdose time point and not present at baseline QT or QTcF \>500 msec at any postdose time point and not present at baseline. QT/QTcF Increase from baseline \>60 msec for at least 1 postdose measurement. Increase from baseline in QT or QTcF \>30 msec for at least 1 postdose measurement, but \<=60 msec for all postdose measurements. |
| Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Baseline to Day 1 of each period | Blood pressure was taken while the participant was quietly seated for at least 5 minutes. Blood pressure was measured in millimeters of mercury (mmHg). Baseline was Day -1 in Period 1; study drug was administered on Day 1 of each crossover period. |
| Half-life (T-HALF) of Dapagliflozin From a Single Dose of Dapagliflozin Versus T-Half of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours. |
| Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. CLT/F was calculated as Dose/AUC(INF)and was measured in milliliters per minute (mL/min). |
| Cmax of 5-Hydroxy (5-OH) Saxagliptin From a Single Dose Saxagliptin Versus Cmax of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). Actual sampling times were used for PK calculations. Cmax for 5-OH Saxagliptin (the major active metabolite of Saxagliptin) was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in ng/mL. |
| AUC(0-T) of 5-OH Saxagliptin From Single Dose Saxagliptin Versus AUC(0-T) of 5-OH From Saxagliptin Co-administered With Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method)and was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™. AUC (0-T) was measured in nanograms\*hours per milliliter (ng\*h/mL). |
| AUC(INF) of 5-OH Saxagliptin From a Single Dose Saxagliptin Versus AUC(INF) of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Day 1 (0h to 60h post dose) in each period | Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL). |
Countries
United States
Participant flow
Recruitment details
20 August 2012 to 29 November 2012. Phase 1 Clinical Pharmacology center with healthy, fasted participants.
Pre-assignment details
89 participants enrolled; 42 randomized and treated with study drug. 47 not randomized for following reasons: 3 withdrew consent, 38 no longer met study criteria, 6 had other reasons. Treatment was administered on Day 1 of each period after fast of 10 hours; Washout began after single dose in the period and was for at least 6 days.
Participants by arm
| Arm | Count |
|---|---|
| A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin) Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral. | 7 |
| A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral. | 7 |
| B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin) Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral | 7 |
| B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral. | 7 |
| C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets,Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral. | 7 |
| C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; Treatment B: Dapagliflozin 10mg, Tablet, Oral; Treatment A: Saxagliptin 5mg, Tablet, Oral. | 7 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 3 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin | Total | A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin) | A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin | B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin) | B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin | C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 42 Participants | 7 Participants | 7 Participants | 7 Participants | 7 Participants | 7 Participants |
| Age, Continuous | 33.3 years STANDARD_DEVIATION 7.95 | 32.0 years STANDARD_DEVIATION 6.81 | 36.1 years STANDARD_DEVIATION 6.47 | 28.7 years STANDARD_DEVIATION 5.02 | 27.7 years STANDARD_DEVIATION 6.99 | 32.0 years STANDARD_DEVIATION 6.51 | 34.4 years STANDARD_DEVIATION 5.74 |
| Body Surface Area (m^2) | 1.85 m^2 STANDARD_DEVIATION 0.108 | 1.91 m^2 STANDARD_DEVIATION 0.16 | 1.90 m^2 STANDARD_DEVIATION 0.187 | 1.92 m^2 STANDARD_DEVIATION 0.145 | 1.91 m^2 STANDARD_DEVIATION 0.208 | 1.95 m^2 STANDARD_DEVIATION 0.17 | 1.94 m^2 STANDARD_DEVIATION 0.166 |
| Body Weight (kg) | 71.71 kg STANDARD_DEVIATION 6.404 | 77.50 kg STANDARD_DEVIATION 10.813 | 77.94 kg STANDARD_DEVIATION 12.25 | 78.94 kg STANDARD_DEVIATION 8.1 | 76.01 kg STANDARD_DEVIATION 14.589 | 80.73 kg STANDARD_DEVIATION 11.903 | 79.64 kg STANDARD_DEVIATION 11.223 |
| Region of Enrollment United States | 7 participants | 42 participants | 7 participants | 7 participants | 7 participants | 7 participants | 7 participants |
| Sex: Female, Male Female | 2 Participants | 13 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 29 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 5 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 | 6 / 42 | 9 / 42 | 8 / 42 |
| serious Total, serious adverse events | 0 / 42 | 0 / 42 | 0 / 42 |
Outcome results
Primary
Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity [AUC(INF)] of Dapagliflozin From a Single Dose of Dapagliflozin Versus AUC (INF) of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population
AUC(INF) is area under the plasma concentration-time curve from time 0 extrapolated to infinity. Serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(INF) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity [AUC(INF)] of Dapagliflozin From a Single Dose of Dapagliflozin Versus AUC (INF) of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 547 ng*h/mL | Geometric Coefficient of Variation 23 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Area Under the Concentration-time Curve (AUC) From Time Zero to Infinity [AUC(INF)] of Dapagliflozin From a Single Dose of Dapagliflozin Versus AUC (INF) of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 539 ng*h/mL | Geometric Coefficient of Variation 20 |
Comparison: Treatment B versus C in AUC(INF). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.961, 1.008]Mixed Models Analysis
Primary
Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus AUC(0-T) for Dapagliflozin When Co-administered With 5 mg Saxagliptin
AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method). Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Actual sampling times were used for PK calculations. AUC(0-T) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus AUC(0-T) for Dapagliflozin When Co-administered With 5 mg Saxagliptin | 529 ng*h/mL | Geometric Coefficient of Variation 23 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Area Under the Concentration-time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-T) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus AUC(0-T) for Dapagliflozin When Co-administered With 5 mg Saxagliptin | 523 ng*h/mL | Geometric Coefficient of Variation 19 |
Comparison: Treatment B versus C in AUC(0-T). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.966, 1.014]Mixed Models Analysis
Primary
AUC(0-T) of Saxagliptin From Single Dose 5 mg Saxagliptin Versus AUC(0-T) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography-Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(0-T), the area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | AUC(0-T) of Saxagliptin From Single Dose 5 mg Saxagliptin Versus AUC(0-T) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 87.8 ng*h/mL | Geometric Coefficient of Variation 23 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(0-T) of Saxagliptin From Single Dose 5 mg Saxagliptin Versus AUC(0-T) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 87.0 ng*h/mL | Geometric Coefficient of Variation 23 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.96, 1.022]Mixed Models Analysis
Primary
AUC(INF) of Saxagliptin From a Single Dose of 5 mg Saxagliptin Versus AUC(INF) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | AUC(INF) of Saxagliptin From a Single Dose of 5 mg Saxagliptin Versus AUC(INF) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 89.0 ng*h/mL | Geometric Coefficient of Variation 23 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(INF) of Saxagliptin From a Single Dose of 5 mg Saxagliptin Versus AUC(INF) of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 88.2 ng*h/mL | Geometric Coefficient of Variation 23 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.961, 1.022]Mixed Models Analysis
Primary
Maximum Observed Concentration (Cmax) of a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by Liquid chromatography-Mass Spectrometry (LC-MS/MS) using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL). Cmax for Saxagliptin was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in nanograms per milliliter (ng/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Maximum Observed Concentration (Cmax) of a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 23.6 ng/mL | Geometric Coefficient of Variation 31 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Maximum Observed Concentration (Cmax) of a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin When Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 21.9 ng/mL | Geometric Coefficient of Variation 33 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.883, 0.972]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin From a Single Dose of Dapagliflozin Versus Cmax of Dapagliflozin From Co-administered Saxagliptin Plus Dapagliflozin - Pharmacokinetic Evaluable Population
The geometric mean of the maximum observed plasma concentration (Cmax) is presented below; serial blood samples for determination of study drug were collected predose (0 hours (h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h,and 60 h postdose, relative to dosing on Day 1 in each cross over period and these data are summarized in the Pharmacokinetic (PK) parameter of Cmax presented here. Plasma samples were analyzed for dapagliflozin by High Performance Liquid chromatography-Mass Spectrometry (HPLC-MS/MS) using a validated method; nominal range of 0.200 to 100 nanograms per milliliter (ng/mL). Dapagliflozin Cmax was derived from plasma concentration versus time data using a non-compartmental method, using a validated PK analysis program ™. Actual sampling times were used for PK calculations. Cmax was reported in ng/mL.
Time frame: Day 1 (0 h to 60 h post dose) in each period
Population: Pharmacokinetic (PK) Evaluable: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin From a Single Dose of Dapagliflozin Versus Cmax of Dapagliflozin From Co-administered Saxagliptin Plus Dapagliflozin - Pharmacokinetic Evaluable Population | 133 ng/mL | Geometric Coefficient of Variation 23 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Maximum Observed Plasma Concentration (Cmax) of Dapagliflozin From a Single Dose of Dapagliflozin Versus Cmax of Dapagliflozin From Co-administered Saxagliptin Plus Dapagliflozin - Pharmacokinetic Evaluable Population | 125 ng/mL | Geometric Coefficient of Variation 27 |
Comparison: The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.867, 1.026]Mixed Models Analysis
Secondary
AUC(0-T) of 5-OH Saxagliptin From Single Dose Saxagliptin Versus AUC(0-T) of 5-OH From Saxagliptin Co-administered With Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method)and was derived from the plasma concentration versus time profile for study drug using a validated PK analysis program ™. AUC (0-T) was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | AUC(0-T) of 5-OH Saxagliptin From Single Dose Saxagliptin Versus AUC(0-T) of 5-OH From Saxagliptin Co-administered With Dapagliflozin - PK Evaluable Population | 267 ng*h/mL | Geometric Coefficient of Variation 22 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(0-T) of 5-OH Saxagliptin From Single Dose Saxagliptin Versus AUC(0-T) of 5-OH From Saxagliptin Co-administered With Dapagliflozin - PK Evaluable Population | 289 ng*h/mL | Geometric Coefficient of Variation 22 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [1.058, 1.113]Mixed Models Analysis
Secondary
AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. AUC(INF) is area under the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-T) is area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (linear up/log down trapezoidal method) and both were derived from the plasma concentration versus time profile using a validated PK analysis program ™. Total moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin), AUC(0-T)and AUC(INF) were measured in nano Molars\*hours (nM\*h).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Dapagliflozin | AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | AUC(INF) for Saxagliptin Total Active Moiety | 702 nM*h | Geometric Coefficient of Variation 15 |
| 10 mg Dapagliflozin | AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | AUC(0-T) for Saxagliptin Total Active Moiety | 694 nM*h | Geometric Coefficient of Variation 15 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | AUC(INF) for Saxagliptin Total Active Moiety | 735 nM*h | Geometric Coefficient of Variation 15 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(INF) and AUC(0-T) of the Saxagliptin Total Active Moiety From a Single Dose 5 mg Saxagliptin Versus AUC(INF) and AUC(0-T) of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | AUC(0-T) for Saxagliptin Total Active Moiety | 727 nM*h | Geometric Coefficient of Variation 15 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the AUC(0-T) of saxagliptin total active moiety. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [1.029, 1.064]Mixed Models Analysis
Secondary
AUC(INF) of 5-OH Saxagliptin From a Single Dose Saxagliptin Versus AUC(INF) of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). AUC(INF) was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in nanograms\*hours per milliliter (ng\*h/mL).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | AUC(INF) of 5-OH Saxagliptin From a Single Dose Saxagliptin Versus AUC(INF) of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | 273 ng*h/mL | Geometric Coefficient of Variation 22 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | AUC(INF) of 5-OH Saxagliptin From a Single Dose Saxagliptin Versus AUC(INF) of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | 296 ng*h/mL | Geometric Coefficient of Variation 22 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [1.058, 1.113]Mixed Models Analysis
Secondary
Cmax of 5-Hydroxy (5-OH) Saxagliptin From a Single Dose Saxagliptin Versus Cmax of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.200 ng/mL to 100.0 ng/mL). Actual sampling times were used for PK calculations. Cmax for 5-OH Saxagliptin (the major active metabolite of Saxagliptin) was derived from plasma concentration versus time data using a validated PK analysis program ™ and was measured in ng/mL.
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Cmax of 5-Hydroxy (5-OH) Saxagliptin From a Single Dose Saxagliptin Versus Cmax of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | 47.0 ng/mL | Geometric Coefficient of Variation 30 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Cmax of 5-Hydroxy (5-OH) Saxagliptin From a Single Dose Saxagliptin Versus Cmax of 5-OH When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | 49.6 ng/mL | Geometric Coefficient of Variation 27 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of 5-OH saxagliptin (metabolite of saxagliptin). The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [1.004, 1.109]Mixed Models Analysis
Secondary
Cmax of the Saxagliptin Total Active Moiety From a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Cmax of saxagliptin total active moiety (molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin) was derived from the plasma concentration versus time profile for the saxagliptin total active moiety. Measurement was in nano Molars (nM).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Cmax of the Saxagliptin Total Active Moiety From a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 138 nM | Geometric Coefficient of Variation 20 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Cmax of the Saxagliptin Total Active Moiety From a Single Dose of 5 mg Saxagliptin Versus Cmax of Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable Population | 137 nM | Geometric Coefficient of Variation 21 |
Comparison: This analysis assesses the effect of concomitant administration of dapagliflozin on the Pharmacokinetics of saxagliptin total active moiety. The statistical model includes treatment and period as fixed effects and measurements within each participant as repeated measurements. The adjusted geometric means are from the mixed model.90% CI: [0.96, 1.03]Mixed Models Analysis
Secondary
Half-life (T-HALF) of Dapagliflozin From a Single Dose of Dapagliflozin Versus T-Half of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours.
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. 1 participant (ACB treatment sequence) withdrew consent after having received all 3 treatments and did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B). This did not impact T-HALF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Half-life (T-HALF) of Dapagliflozin From a Single Dose of Dapagliflozin Versus T-Half of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 15.9 hours | Standard Deviation 7.32 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Half-life (T-HALF) of Dapagliflozin From a Single Dose of Dapagliflozin Versus T-Half of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 13.8 hours | Standard Deviation 4.81 |
Secondary
Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin by LC-MS/MS using a validated method. T-HALF was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours (h).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Dapagliflozin | Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population | T-HALF for Saxagliptin | 5.86 h | Standard Deviation 2.23 |
| 10 mg Dapagliflozin | Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population | T-HALF for 5-OH Saxagliptin | 15.9 h | Standard Deviation 3.06 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population | T-HALF for Saxagliptin | 5.38 h | Standard Deviation 2.17 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Half-life (T-HALF) of Saxagliptin, and 5-OH Saxagliptin From Single Dose 5 mg Saxagliptin Versus T-HALF of Saxagliptin and 5-OH From Co-administered Saxagliptin With 10 mg Dapagliflozin - PK Evaluable Population | T-HALF for 5-OH Saxagliptin | 17.0 h | Standard Deviation 2.97 |
Secondary
Mean Change From Baseline in Heart Rate - Safety Population
Heart rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in beats per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time frame: Baseline to Day 1 in each period
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Mean Change From Baseline in Heart Rate - Safety Population | -4.4 bpm | Standard Deviation 7.04 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Mean Change From Baseline in Heart Rate - Safety Population | -4.0 bpm | Standard Deviation 9.64 |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Mean Change From Baseline in Heart Rate - Safety Population | -4.3 bpm | Standard Deviation 10.52 |
Secondary
Mean Change From Baseline in Respiration Rate - Safety Population
Respiration rates were taken while the participant was sitting quietly for at least 5 minutes and were measured in breaths per minute (bpm). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time frame: Baseline to Day 1 in each period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Mean Change From Baseline in Respiration Rate - Safety Population | -0.4 bpm | Standard Deviation 3.46 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Mean Change From Baseline in Respiration Rate - Safety Population | -1.2 bpm | Standard Deviation 2.89 |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Mean Change From Baseline in Respiration Rate - Safety Population | -0.9 bpm | Standard Deviation 3.13 |
Secondary
Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population
Blood pressure was taken while the participant was quietly seated for at least 5 minutes. Blood pressure was measured in millimeters of mercury (mmHg). Baseline was Day -1 in Period 1; study drug was administered on Day 1 of each crossover period.
Time frame: Baseline to Day 1 of each period
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Dapagliflozin | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Systolic Blood Pressure | -6.0 mmHg | Standard Deviation 7.41 |
| 10 mg Dapagliflozin | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Diastolic Blood Pressure | -2.6 mmHg | Standard Deviation 4.94 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Systolic Blood Pressure | -4.6 mmHg | Standard Deviation 8.13 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Diastolic Blood Pressure | -2.0 mmHg | Standard Deviation 4.86 |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Systolic Blood Pressure | -7.2 mmHg | Standard Deviation 8.35 |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Mean Change From Baseline in Systolic and Diastolic Blood Pressure - Safety Population | Diastolic Blood Pressure | -3.3 mmHg | Standard Deviation 6.23 |
Secondary
Mean Change From Baseline in Temperature - Safety Population
Participant had their temperature taken after quietly sitting for at least 5 minutes and it was measured as degrees of centigrade (C). Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period.
Time frame: Baseline to Day 1 in each period
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Mean Change From Baseline in Temperature - Safety Population | -0.15 degrees of centigrade | Standard Deviation 0.393 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Mean Change From Baseline in Temperature - Safety Population | -0.23 degrees of centigrade | Standard Deviation 0.383 |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Mean Change From Baseline in Temperature - Safety Population | -0.16 degrees of centigrade | Standard Deviation 0.385 |
Secondary
Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Saxagliptin is the parent drug and 5-OH saxagliptin is the metabolite. The molecular weights to be used for the molar ratios were 315.42 and 331.42 for saxagliptin and 5-OH, respectively. Plasma samples were analyzed for saxagliptin and for 5-OH by LC-MS/MS using a validated method (quantitation range of 0.100 ng/mL to 50.0 ng/mL and 0.200 ng/mL to 100.0 ng/mL for saxagliptin and 5-OH, respectively).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_Cmax | 1.90 Molar ratio | Geometric Coefficient of Variation 37 |
| 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_AUC(INF) | 2.92 Molar ratio | Geometric Coefficient of Variation 33 |
| 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_AUC(0-T) | 2.89 Molar ratio | Geometric Coefficient of Variation 33 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_Cmax | 2.16 Molar ratio | Geometric Coefficient of Variation 37 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_AUC(INF) | 3.19 Molar ratio | Geometric Coefficient of Variation 33 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Metabolite to Parent Molar Ratios (MR) of Cmax, AUC(INF), and AUC(0-T) of 5-OH Saxagliptin and Saxagliptin From a Single Dose 5 mg Saxagliptin Versus MR of Saxagliptin and 5-OH When Saxagliptin Was Co-administered With 10 mg Dapagliflozin - PK Evaluable | MR_AUC(0-T) | 3.16 Molar ratio | Geometric Coefficient of Variation 34 |
Secondary
Number of Participants With Change From Baseline in ECG Interval - Safety Population
A 12-Lead electrocardiogram (ECG) was performed and recorded after the participant had been supine for at least 5 minutes. ECGs done at baseline (Day-1 of Period 1) and at end of study; therefore the results are presented by sequence, and cannot be presented by treatment. QT interval (measure between Q wave and T wave in the heart's electrical cycle); and QT interval corrected for heart rate using Fridericia's formula (QTcF) were measured in milliseconds (msec). Abnormality criteria: QT/QTcF QT or QTcF \>450 msec and \<=480 msec at any postdose time point and not present at baseline. QT or QTcF \>480 msec and \<=500 msec at any postdose time point and not present at baseline QT or QTcF \>500 msec at any postdose time point and not present at baseline. QT/QTcF Increase from baseline \>60 msec for at least 1 postdose measurement. Increase from baseline in QT or QTcF \>30 msec for at least 1 postdose measurement, but \<=60 msec for all postdose measurements.
Time frame: Baseline to end of study (16 days)
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 4 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 0 participants |
| B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 1 participants |
| B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 0 participants |
| B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 0 participants |
| C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 0 participants |
| C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >30 msec; <=60 msec | 0 participants |
| C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >60 msec | 0 participants |
| C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QTcF change from baseline >30 msec; <=60 msec | 0 participants |
| C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin | Number of Participants With Change From Baseline in ECG Interval - Safety Population | QT change from baseline >60 msec | 0 participants |
Secondary
Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population
Adverse event (AE)=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious adverse event (SAE)=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. End of study was approximately 16 days and was the time for a participant to conclude each of the 3 periods (including the 6 day washout between periods).
Time frame: Day 1 to end of study (16 days)
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants discontinuing due to AEs | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with SAEs | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with AEs | 6 participants |
| 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with treatment-related AEs | 4 participants |
| 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Deaths | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with SAEs | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with AEs | 9 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with treatment-related AEs | 4 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants discontinuing due to AEs | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Deaths | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Deaths | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants discontinuing due to AEs | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with AEs | 8 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with SAEs | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Deaths, Serious Adverse Events, Adverse Events, or Discontinuations Due to Adverse Events - Safety Population | Participants with treatment-related AEs | 7 participants |
Secondary
Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population
Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal(LLN); upper limit of normal (ULN); pre-treatment(Pre-Rx). Alkaline phosphatase U/L:\>1.25\*Pre-RX if Pre-Rx \>ULN or \>1.25\*ULN if Pre-Rx \<=ULN; aspartate aminotransferase (AST) U/L: \>1.25\*Pre-Rx if Pre-Rx \> ULN or 1.25\*ULN if Pre-Rx \<= ULN;alanine aminotransferase (ALT) U/L: \>1.25\*Pre-Rx if Pre-Rx\>ULN or 1.25\*ULN if Pre-Rx\<=ULN;blood urea nitrogen (BUN)mmol/L: \>1.1\*ULN if Pre-Rx \<=ULN or \>1.2\*Pre-Rx if Pre-Rx \>ULN; total bilirubin µmol/L: \>1.1\*ULN if Pre-Rx \<=ULN or \>1.25\*Pre-Rx if Pre-Rx \>ULN;direct bilirubin µmol/L: \>1.1\*ULN if Pre-Rx \<= ULN or \>1.25\*Pre-Rx if Pre-Rx \> ULN; creatine phosphokinase (CK) U/L: \>1.5\*Pre-Rx if Pre-Rx \>ULN or \>1.5\*ULN if Pre-Rx \<= ULN.
Time frame: Baseline to Day 1 in each period
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | BUN High | 1 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | ALT High | 1 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Total Bilirubin High | 1 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Direct Bilirubin High | 1 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | CK High | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | ALT High | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Total Bilirubin High | 1 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Direct Bilirubin High | 1 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | BUN High | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | CK High | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | CK High | 1 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | BUN High | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Total Bilirubin High | 1 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | ALT High | 1 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Chemistry Laboratory Abnormalities - Safety Population | Direct Bilirubin High | 1 participants |
Secondary
Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population
Fasted for 10 hours prior to samples taken. Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Lower limit of normal (LLN); upper limit of normal (ULN); pretreatment(pre-RX); treatment (RX). Hemoglobin (g/L): \<0.85\* pre-RX; hematocrit (vol): \<0.85\*pre-RX; erythrocytes (\*10\^12 c/L): \<0.85\*pre-RX; platelet count (\*10\^9 c/L): \<0.85\*LLN if pre-RX\>=LLN, or if Pre-Tx \<LLN; leukocytes (\*10\^9 c/L): \<0.85\*LLN if pre-RX \<LLN,or \<0.9\*LLN if LLN\<=Pre-RX\<=ULN; neutrophils+bands (\*10\^9 c/L): \<0.85\*Pre-RX if Pre-RX \<1.5 or \<1.5 if Pre-RX \>=1.5; eosinophils (\*10\^9 c/L): if value \>0.75; basophils (\*10\^9 c/L): if value \>0.4; monocytes (\*10\^9c/L): if value \>2; lymphocytes (\*10\^9 c/L): if value \<0.750 or if value \>7.50.
Time frame: Baseline to Day 1 of each period
Population: Safety Population = All participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Dapagliflozin | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Leukocytes Low | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Neutrophils (absolute) Low | 1 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Leukocytes Low | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Neutrophils (absolute) Low | 1 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Leukocytes Low | 1 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Hematology Laboratory Abnormalities - Safety Population | Neutrophils (absolute) Low | 1 participants |
Secondary
Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population
Baseline was Day -1 of Period 1; study drug was administered on Day 1 of each crossover period. Fasted for 10 hours prior to samples taken. LLN=lower limit of normal; ULN=upper limit of normal; pretreatment (Pre-Rx). Normals: Urine glucose qualitative: dipstick \>=1 if Pre-Rx \<1 or 2\*Pre-Rx if Pre-Rx\>=1; urine microscopic white blood cell count (WBC): \>=2 if Pre-Rx \<2 or \>=4 if Pre-Rx \>=2;urine red blood cell count (RBC):\>=2 if Pre-Rx \<2 or \>=4 if Pre-Rx \>=2.
Time frame: Baseline to Day 1 of each period
Population: Safety Population = All participants who received at least one dose of any study drug. Urine WBC and RBC were not done for all 42 participants. Number of participants analyzed (N) for the 3 treatments for WBC/RBC urine were 4, 8, 6, in treatment A, B, C, respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Dapagliflozin | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine Glucose High (N=42, 42, 42) | 0 participants |
| 10 mg Dapagliflozin | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine WBC and RBC High (N= 4, 8, 6) | 0 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine Glucose High (N=42, 42, 42) | 2 participants |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine WBC and RBC High (N= 4, 8, 6) | 0 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine Glucose High (N=42, 42, 42) | 5 participants |
| Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg | Number of Participants With Marked Urinalysis Laboratory Abnormalities - Safety Population | Urine WBC and RBC High (N= 4, 8, 6) | 1 participants |
Secondary
Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. CLT/F was calculated as Dose/AUC(INF)and was measured in milliliters per minute (mL/min).
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. One participant in the ACB treatment sequence withdrew consent after having received all 3 treatments; this participant did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Dapagliflozin | Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 305 mL/min | Geometric Coefficient of Variation 24 |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Plasma Apparent Clearance (CLT/F) of a Single Dose of Dapagliflozin Versus CLT/F of Dapagliflozin When Co-administered With Saxagliptin - PK Evaluable Population | 309 mL/min | Geometric Coefficient of Variation 20 |
Secondary
Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus Tmax of Dapagliflozin When Co-administered With 5 mg Saxagliptin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for dapagliflozin by HPLC-MS/MS using a validated method. Actual sampling times were used for PK calculations. Tmax was derived from the plasma concentration versus time profile using a validated PK analysis program ™ and was measured in hours.
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte. 1 participant (ACB treatment sequence) withdrew consent after having received all 3 treatments and did not provide 36-, 48-, or 60-hour samples in Period 3 (Treatment B). This did not impact T-HALF.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 10 mg Dapagliflozin | Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus Tmax of Dapagliflozin When Co-administered With 5 mg Saxagliptin - PK Evaluable Population | 1.00 hours |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Time of Maximum Observed Plasma Concentration (Tmax) of Dapagliflozin From a Single Dose of 10 mg Dapagliflozin Versus Tmax of Dapagliflozin When Co-administered With 5 mg Saxagliptin - PK Evaluable Population | 1.00 hours |
Secondary
Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population
Serial blood samples for determination of study drug were collected predose (0 h), 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h and 60 h postdose, relative to dosing on Day 1 in each cross over period. Plasma samples were analyzed for saxagliptin and 5-OH by LC-MS/MS using a validated method. Tmax was derived from the plasma concentration versus time profile for study drug and was measured in hours (h). Saxagliptin was the drug, 5-OH saxagliptin was the metabolite, and Saxagliptin total Active Moiety was molar summations of saxagliptin exposure parameter with one-half the molar exposure parameters for 5-OH Saxagliptin.
Time frame: Day 1 (0h to 60h post dose) in each period
Population: PK Evaluable Population: All participants who received at least 1 dose of any study drug and had at least 1 valid PK parameter for at least 1 analyte.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of Saxagliptin | 0.50 h |
| 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of 5-OH Saxagliptin | 1.50 h |
| 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of Saxagliptin Total Active Moiety | 1.00 h |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of Saxagliptin | 1.00 h |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of 5-OH Saxagliptin | 1.50 h |
| 5 mg Saxagliptin + 10 mg Dapagliflozin | Tmax of Saxagliptin, 5-OH Saxagliptin, Saxagliptin Total Active Moiety From a Single Dose of Saxagliptin Versus Tmax of Saxagliptin, 5-OH, Saxagliptin Total Active Moiety When Saxagliptin Was Co-administered With Dapagliflozin - PK Evaluable Population | Tmax of Saxagliptin Total Active Moiety | 1.00 h |