Bioequivalence Study of Saxagliptin and Glucophage Combination Formulations in Healthy Subjects (B)

• Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
• Saxagliptin PK Parameter Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUC[0-T]) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
• Saxagliptin PK Parameter Maximum Observed Plasma Concentration (Cmax) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
• Saxagliptin PK Parameter Plasma Terminal Half-life (T-HALF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
• Saxagliptin PK Parameter Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data.
• Metformin PK Parameter AUC(INF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
• Metformin PK Parameter AUC(0-T) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
• Metformin PK Parameter Cmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
• Metformin PK Parameter T-HALF [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of metformin were derived from plasma concentration versus time data.
• Metformin PK Parameter Tmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of metformin were derived from plasma concentration versus time data.

• BMS-510849 PK Parameter AUC(INF) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
• BMS-510849 PK Parameter AUC(0-T) [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
• BMS-510849 PK Parameter Cmax [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
• BMS-510849 PK Parameter T-Half [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from their respective plasma concentration versus time data.
• BMS-510849 PK Parameter T-Max [ Time Frame: pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period ] [ Designated as safety issue: No ]
  Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data.
• Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuations Due to AEs [ Time Frame: AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). SAEs collected from date of written consent until 30 days post discontinuation of dosing or subject's participation in the study. ] [ Designated as safety issue: Yes ]
  An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.
• AEs of Special Interest [ Time Frame: AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). ] [ Designated as safety issue: Yes ]
  See Outcome Measure 16 for a definition of AEs. AEs of clinical interest for saxagliptin were defined as those relating to the following:skin disorders, infection-related AEs (system organ class [SOC]: Infections and Infestations), thrombocytopenia, lymphopenia, hypoglycemia, cardiovascular AEs indicative of acute cardiovascular events, localized edema, fractures, pancreatitis, and AEs of hypersensitivity.
• Number of Participants With Marked Laboratory Abnormalities (MA) [ Time Frame: Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. ] [ Designated as safety issue: Yes ]
  Laboratory abnormalities=any result that is clinically significant, met the definition of an SAE, required discontinuation or interruption of study drug, or required specific corrective therapy. Upper normal (UN)/lower normal (LN) values: leukocytes UN, 11.40x10^3 c/uL; absolute neutrophils/bands LN, 1.500x10^3 c/uL; aspartate aminotransferase UN, 48 U/L; alanine aminotransferase UN, 67 U/L; blood urea nitrogen UN, 20.0 mg/dL; creatine kinase UN, 350 U/L; lactate dehydrogenase UN, 249 U/L.
• Number of Participants With Marked Urinalysis Abnormalities [ Time Frame: Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. ] [ Designated as safety issue: Yes ]
  Protein, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Glucose, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Blood, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). White Blood Cell (WBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). Red Blood Cell (RBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). (The '+' is a normal lab result and refers to the magnitude of the finding.)
• Electrocardiogram (ECG), Vital Sign, and Physical Finding Abnormalities [ Time Frame: At Screening (within 21 days of Study Day 1), Day -1 of Period 1 (ECG and Physical only), Day 1 of Periods 1-4 (Vitals only), at Study Discharge (Day 3 of Period 4) or Discontinuation ] [ Designated as safety issue: Yes ]
  12-lead Electrocardiogram (ECG), Vital Sign (body temperature, respiratory rate, seated blood pressure and heart rate), and Physical Finding Abnormalities reported by investigator as AEs.

• To assess the PK of the active metabolite of saxagliptin, BMS-510849, when saxagliptin is co-administered with a metformin IR tablet and in a FDC tablet with metformin IR under fasted and under fed condition in healthy subjects [ Time Frame: 14 time points up to 24 hours after dosing ] [ Designated as safety issue: Yes ]
• To assess the safety and tolerability of 2.5 mg saxagliptin when co-administered with a 1000 mg metformin IR tablet and in a FDC tablet with metformin IR under fasted and under fed condition in healthy subjects [ Time Frame: 14 time points up to 24 hours after dosing (saxagliptin)/16 time points up to 48 hours after dosing (Metformin)] ] [ Designated as safety issue: Yes ]

To demonstrate bioequivalence of a 2.5 mg saxagliptin/1000 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 1000 mg metformin IR tablet co-administered to healthy subjects in a fasted and in a fed state.

• Drug: Saxagliptin
  Tablet, Oral, 2.5 mg, Once Daily, 1 week
  Other Name: Onglyza
• Drug: Metformin IR (glucophage)
  Tablets, Oral, 1000 mg, Once Daily, 1 week
  Other Name: Glucophage
• Drug: Saxagliptin + Metformin IR (FDC)
  Tablet, Oral, Saxagliptin 2.5 mg + metformin IR 1000 mg, Once Daily, 1 Week
  Other Names:

  • Onglyza
  • Glucophage

• Arm A
  Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fasted conditions
  Interventions:

  • Drug: Saxagliptin
  • Drug: Metformin IR (glucophage)
• Arm B
  Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fasted conditions
  Intervention: Drug: Saxagliptin + Metformin IR (FDC)
• Arm C
  Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fed conditions with a standard meal
  Interventions:

  • Drug: Saxagliptin
  • Drug: Metformin IR (glucophage)
• Arm D
  Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fed conditions with a standard meal
  Intervention: Drug: Saxagliptin + Metformin IR (FDC)

Inclusion Criteria:

• Men and women ages 19 to 45 inclusive
• Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations
• Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive. BMI = weight (kg)/ [height (m)]2

Exclusion Criteria:

• Women of child-bearing potential (WOCBP) who are unwilling or unable to use acceptable barrier methods (condoms and spermicides) to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of investigational product
• Any significant acute or chronic medical illness
• Current or recent (within 3 months) gastrointestinal disease
• Any major surgery within 4 weeks of study drug administration
• History of allergy to Dipeptidyl peptidase 4 (DPP4) inhibitor or related compounds
• History of allergy or intolerance to metformin or other similar acting agents
• Prior exposure to saxagliptin
• Prior exposure to metformin within 3 months of study drug administration
• Estimated creatinine clearance (Clcr) of < 80ml/min using the Cockcroft Gault formula