A Two-Cohort, Single- and Repeat Dose Study to Examine the Pharmacokinetics, Tolerability, and Safety of Ready to Use Exenatide Once Weekly in Healthy Subjects and in Subjects With Type 2 Diabetes Mellitus

Area Under the Curve (AUC) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population

时间窗: Day 1, Week 12

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 and the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. AUC was measured in picograms \* hours per milliliter (pg\*hr/mL). Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y; AUC (0-8h) and (0-tlast) are presented below. Pharmacokinetic (PK) evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] from Day 1 to Week 12 and had reliable PK data.

Maximum Concentration (Cmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population

时间窗: Day 1, Week 12

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 and the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Cmax was measured in picograms per milliliter (pg/mL). Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] from Day 1 to Week 12 for the evaluation of the PK characteristics of plasma exenatide and had reliable PK data. Cmax (0-8h) and (0-tlast) are presented below.

Time to Maximum Concentration (Tmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population

时间窗: Day 1, Week 12

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time(t) = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 an the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Tmax was measured in hours and Tmax (0-8h) and (0-tlast) are presented below. Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] and had reliable PK data.

Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population

时间窗: Day 1 to Week12

Treatment emergent (TE)=occurs during or after treatment with study drug. 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. 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. Participants experiencing multiple episodes of a given AE are counted once. Injection site AEs: adverse events that existed prior to Day 1 and worsened after the first administration at Day 1, or occurred after the first administration at Day 1 through Week 12, or after Study Termination if considered by investigator to be clinically significant.

Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population

时间窗: Day 1 to 12 weeks

Concomitant medications are defined as those medications received on or after the date of the first injection on Day 1, including prior medications that continued past Day 1 and new concomitant medications. Participants may be counted in more than one medication class and no more than once in each class. Categories by Anatomical Therapeutic Chemical (ATC) classification using the World Health Organization (WHO) Drug Dictionary version C1, 01 March 2009. As per protocol, all participants in Cohort 1 could receive up to 2 anti-emetic medications approximately 30 minutes prior to the exenatide.

Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population

时间窗: Day 1 to Week 12

In Cohort 1, sitting blood pressures were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-11 (Visits 3-13), Week 12 (Visit 14), and at early termination. Blood pressures (diastolic and systolic) were measured in millimeters of mercury (mmHg). In Cohort 2, sitting blood pressures were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-10 (Visits 3-12), Week 11 (Visit 15), Week 12 (Visit 16) and at early termination. Baseline was defined as last measurement prior to first injection of study drug.

Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population

时间窗: Day 1 to Week 12

In Cohort 1, sitting heart rates were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-11 (Visits 3-13), Week 12 (Visit 14), and at early termination. Heart rate was measured in beats per minute (bpm). In Cohort 2, sitting heart rates were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-10 (Visits 3-12), Week 11 (Visit 15), Week 12 (Visit 16) and at early termination. Baseline was defined as last measurement prior to first injection of study drug.

Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population

时间窗: Day 1 to Week 12

Abbreviations: Upper Limit of Normal (ULN); milligram per deciliter (mg/dL); units per liter (U/L); micro liters (µL); creatine kinase (CK); gamma-glutamyltransferase (G-GT). Normal ranges = Hematocrit: 40.6-52.3% (male), 35.3-47.0 (female); Platelets 155-361\*10\^3/µL(male/female); Calcium: 8.6-10.4 mg/dL (male/female); CK: 43-350 U/L (male), 28-207 U/L (female); G-GT: 7-62 U/L (male/female); Glucose 73-105 mg/dL (male/female); Lipase 14-70 U/L (male/female); Uric acid: 3.5-7.8 mg/dL (male), 2.3-5.9 mg/dL (female). Blood samples for laboratories were collected at screening, Day 1, Weeks 4, 8, 12 or early termination. Value for potential clinical importance is presented in each category presented below.

Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2

时间窗: Day 1 to Week 12

Serum titers of antibodies to exenatide were evaluated using a validated enzyme-linked immunosorbent assay (Covance Method No. ELISA-0308). Positive antibody to exenatide titer: observed at the indicated visit following a negative or missing titer at baseline, or a positive titer that has increased by at least 3 dilutions at the indicated visit from a detectable baseline. Baseline=Day 1. Negative titers were assigned a value of 1 in order to calculate geometric mean. Geometric mean of reportable titers, by study week, are presented below.

Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population

时间窗: Week 10-11; Weeks 10 - 12

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. AUC was measured in picograms \* hours per milliliter (pg\*hr/mL). Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y; AUC (0-6h) measured at Week 10, AUC (0-168h) steady state measured between Weeks 10 and 11, and AUC (0-tlast) for time interval between Weeks 10 and 12 (approximately336 hours) are presented below. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Average Exenatide Concentration (Cave) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population

时间窗: Week 10 - Week 11; Week 10 - Week 12

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Cave(0-168h) and Cave(0-tlast) was the time-weighted mean concentration over the sampling period from time x to time y corresponding to AUC (0-168h), and AUC (0-tlast), respectively. Cave was measured in picograms per milliliter (pg/mL). Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population

时间窗: Week 10, Weeks 10-11, Weeks 10-12

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. Cmax was measured in pg/mL. Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). Cmax summarized at 0-6 h at Week 10, 0-168 h at Weeks 10-11, and 0-tlast at Weeks 10-12. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population

时间窗: Week 10, Weeks 10-11, Weeks 10-12

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. Tmax was measured in hours (h). Exenatide was measured using a validated ELISA. Tmax summarized at 0-6 h at Week 10, 0-168 h at Weeks 10-11, and 0-tlast at Weeks 10-12. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.