Drug Interaction Study of Saxagliptin in Combination With Dapagliflozin in Healthy Participants

Phase 1

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: Saxagliptin
Drug: Dapagliflozin

Registration Number: NCT01662999

Lead Sponsor: AstraZeneca

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin	Saxagliptin	Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose
C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin	Saxagliptin	Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose
B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)	Saxagliptin	Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose. Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose
B-A-C: Dapagliflozin-Saxagliptin-(Saxagliptin+Dapagliflozin)	Dapagliflozin	Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose. Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose
A-C-B: Saxagliptin-(Saxagliptin+Dapagliflozin)-Dapagliflozin	Dapagliflozin	Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose
A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)	Saxagliptin	Treatment A: Saxagliptin 5mg, Tablet, Oral; Single dose Treatment B: Dapagliflozin 10mg, Tablet, Oral; single dose Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; single dose
A-B-C: Saxagliptin-Dapagliflozin-(Saxagliptin+Dapagliflozin)	Dapagliflozin	Treatment A: Saxagliptin 5mg, Tablet, Oral; Single dose Treatment B: Dapagliflozin 10mg, Tablet, Oral; single dose Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral; single dose
B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin	Saxagliptin	Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose
C-A-B: (Saxagliptin+Dapagliflozin)-Saxagliptin-Dapagliflozin	Dapagliflozin	Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose
B-C-A: Dapagliflozin-(Saxagliptin+Dapagliflozin)-Saxagliptin	Dapagliflozin	Treatment B: Dapagliflozin 10mg, Tablet, Oral, single dose; Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose
C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin	Dapagliflozin	Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, Once daily, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose
C-B-A: (Saxagliptin+Dapagliflozin)-Dapagliflozin-Saxagliptin	Saxagliptin	Treatment C: Saxagliptin 5 mg + Dapagliflozin 10 mg, Tablets, Oral, single dose; Treatment B: Dapagliflozin 10mg, Tablet, Oral, Once daily, single dose; Treatment A: Saxagliptin 5mg, Tablet, Oral, single dose

Primary Outcome Measures

Name	Time	Method
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 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).
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).
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 Outcome Measures

Name	Time	Method
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.
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).
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.
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.
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.
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.
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).
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.
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).
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 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.