Clinical Pharmacology
Conditions
Brief summary
This is a randomized, open-label, crossover study to determine the effect of food when a combination tablet of SYR-322 and metformin hydrochloride ( hereinafter referred to as SYR-322-MET tablet) is orally administered under fasting conditions in the morning or after breakfast in Japanese healthy adult male subjects.
Detailed description
The primary objective of this clinical trial is to determine the effect of food on the pharmacokinetics of single oral dose administration of SYR-322-MET tablets in Japanese healthy adult male subjects
Interventions
DRUGSYR-322-MET
Oral administration of SYR-322-MET
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
1. In the opinion of the investigator or subinvestigator, the subject is capable of understanding and complying with protocol requirements. 2. The subject signs and dates a written, informed consent form prior to the initiation of any study procedures. 3. The subject is a Japanese healthy adult male. 4. The subject is aged 20 to 35 years, inclusive, at the time of informed consent. 5. The subject has a body weight of 50 kg or more with a BMI of ≥18.5 kg/m2 and \<25.0 kg/m2 at screening.
Exclusion criteria
1. The subject has received any investigational compound within 16 weeks (112 days) prior to the start of study drug administration in Period 1. 2. The subject has received SYR-322 or metformin hydrochloride in a previous clinical study or as a therapeutic agent. 3. The subject is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 4. The subject has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, or endocrine disease or other abnormality, which may impact the ability of the subject to participate or potentially confound the study results. 5. The subject has a known hypersensitivity to drugs. 6. The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at screening. 7. The subject has a history of drug abuse or history of alcohol abuse within 2 years prior to the screening visit or unwilling to agree to abstain from alcohol and drugs throughout the study. 8. Subject has taken any excluded medication, supplements, or food products during the time periods listed in the Excluded Medications and Dietary Products table. 9. Subject has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the subject's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking DPP-4 inhibitors or biguanides, or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias. 10. The subject has current or recent \[within 24 weeks (168 days) prior to the initiation of study treatment in Period 1\] gastrointestinal disease that would be expected to influence the absorption of drugs (i.e., a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[more than once per week\] occurrence of heartburn, or any surgical intervention \[e.g., cholecystectomy\]). 11. The subject has a history of cancer. 12. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen, or serological reactions for syphilis at screening. 13. The subject has poor peripheral venous access. 14. The subject has undergone whole blood collection of at least 200 mL within 4 weeks (28 days) or at least 400 mL within 12 weeks (84 days) prior to the start of study medication administration Period 1. 15. The subject has undergone whole blood collection of at least 800 mL in total within 52 weeks (364 days) prior to the start of study medication administration in Period 1. 16. The subject has undergone blood component collection within 2 weeks (14 days) prior to the start of study medication administration in Period 1. 17. The subject has a screening or prior to the start of study medication administration on Day 1 in Period 1 hemoglobin level \<12.5 g/dL. 18. The subject has a screening or prior to the start of study medication administration on Day 1 in Period 1 abnormal (clinically significant) 12-lead ECG. 19. Subject has abnormal screening or prior to the start of study medication administration on Day 1 in Period 1 laboratory values that suggest a clinically significant underlying disease or subject with the following lab abnormalities: ALT and/or AST \>1.5 the upper limits of normal. 20. Subject who, in the opinion of the investigator, is unlikely to comply with the protocol or is unsuitable for any other reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CLr: Renal Clearance of Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | CLr is a measure of apparent clearance of the drug from the urine. |
| Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose | 0 to 48 hours postdose | Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose | 0 to 72 hours postdose | Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose | 0 to 12 hours postdose | Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose | 0 to 24 hours post dose | Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose | 0 to 48 hours postdose | Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose | 0 to 72 hours postdose | Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose | 0 to 12 hours postdose | Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose. |
| Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose | 0 to 24 hours postdose | Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose. |
| Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose | 0 to 48 hours postdose | Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose. |
| CLr: Renal Clearance of SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | CLr is a measure of apparent clearance of the drug from the urine. The clearance is the rate at which waste substances are cleared from the blood. |
| MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule. |
| AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z) | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose. |
| AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]). |
| Cmax: Maximum Observed Plasma Concentration for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. |
| AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. |
| Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. |
| Terminal Phase Elimination Half-life (T1/2) for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
| Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z | 3 hours prior to administration, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours after administration | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in liter/hour (L/hr). |
| Mean Residence Time (MRT) for SYR-322Z | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). (AUMC \[0-inf\]) is the area under the first moment plasma concentration-time curve from time 0 to infinity. |
| AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose. |
| AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]). |
| MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule. |
| Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. |
| AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. |
| Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. |
| Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
| Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose | Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity. |
| AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | AUC (0-48) is measure of area under the curve from time 0 to 48 hours post dose. |
| AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]). |
| MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule. |
| Cmax: Maximum Observed Plasma Concentration for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. |
| AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. |
| Apparent Terminal Elimination Rate Constant (λz) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. |
| Terminal Phase Elimination Half-life (T1/2) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. |
| Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in L/hr. |
| Mean Residence Time (MRT) for Metformin | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose | Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity. |
| Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose | 0 to 12 hours postdose | Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose. |
| Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose | 0 to 24 hours postdose | Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DPP-4 Activity | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose | DPP-4 activity was assessed from the plasma samples collected from the participants. |
| AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose | Area under the inhibition rate of plasma DPP-4 activity-time curve from time 0 to 24 hours was determined from the inhibition-time curve. |
| Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose | Maximum inhibition rate of plasma DPP-4 activity was determined from the inhibition-time curve. |
| Tmax: Time to Reach Emax | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose | Time to reach Emax for the first time was determined from the inhibition-time curve. |
| Number of Participants Reporting 1 or More Treatment-emergent Adverse Events | Baseline up to the day of discharge (Day 4) in the second intervention period | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose | Vital signs included body temperature (infra-axillary), supine blood pressure resting more than 5 minutes (systolic and diastolic \[Millimeters of mercury\]), respiratory rate and pulse (beats per minute). Clinically significant change in vital signs observed at any time point are reported. |
| Number of Participants With Clinically Significant Change From Baseline in Body Weight | 3 hours prior to administration (predose), 24 and 72 hours postdose | Clinically significant change participant's body weight observed at any time point are reported. |
| Number of Participants With Significant Change From Baseline in Electrocardiograms | 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose | Clinically significant change in electrocardiograms observed at any time point are reported. |
| Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs) | 3 hours prior to administration (predose), 24 and 72 hours postdose | Laboratory assessments included hematology, serum chemistry and urinalysis. Any laboratory-related TEAE reported at any time point were reported in this measure. |
| Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose | DPP-4 activity and inhibition rate of DPP-4 activity was assessed from the plasma samples collected from the participants. Inhibition of DPP-4 enzyme was used to determine the antihyperglycemic activity of the investigational product. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in Japan from 21 June 2014 to 22 July 2014.
Pre-assignment details
Healthy participants were enrolled in 1 of 2 treatment groups: SYR-322-MET fasted followed by SYR-322-MET fed; SYR-322-MET fed followed by SYR-322-MET fasted.
Participants by arm
| Arm | Count |
|---|---|
| SYR-322-MET Fasted Followed by SYR-322-MET Fed A single dose of SYR-322 25 milligram (mg) and metformin hydrochloride 500 mg in 1 tablet, orally under fasted condition on Day 1 of first intervention period, followed by at least 15 days of washout period, followed by a single dose of SYR-322 25 mg and metformin hydrochloride 500 mg in 1 tablet, orally under fed condition on Day 1 of second intervention period. | 6 |
| SYR-322-MET Fed Followed by SYR-322-MET Fasted A single dose of SYR-322 25 mg and metformin hydrochloride 500 mg in 1 tablet, orally under fed condition on Day 1 of first intervention period, followed by at least 15 days of washout period, followed by a single dose of SYR-322 25 mg and metformin hydrochloride 500 mg in 1 tablet, orally under fasted condition on Day 1 of second intervention period. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | SYR-322-MET Fasted Followed by SYR-322-MET Fed | SYR-322-MET Fed Followed by SYR-322-MET Fasted | Total |
|---|---|---|---|
| Age, Continuous | 23.2 years STANDARD_DEVIATION 1.94 | 27.2 years STANDARD_DEVIATION 6.43 | 25.2 years STANDARD_DEVIATION 4.99 |
| Alcohol Classification Drank a Few Days per Month | 4 participants | 3 participants | 7 participants |
| Alcohol Classification Drank a Few Days per Week | 0 participants | 0 participants | 0 participants |
| Alcohol Classification Drank Every Day | 0 participants | 0 participants | 0 participants |
| Alcohol Classification No | 2 participants | 3 participants | 5 participants |
| Body Mass Index (BMI) | 21.48 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.878 | 21.15 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 0.869 | 21.32 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.406 |
| Caffeine Classification Did not take Caffeine | 4 participants | 5 participants | 9 participants |
| Caffeine Classification Took Caffeine | 2 participants | 1 participants | 3 participants |
| height | 168.5 centimeters (cm) STANDARD_DEVIATION 6.98 | 175.7 centimeters (cm) STANDARD_DEVIATION 6.68 | 172.1 centimeters (cm) STANDARD_DEVIATION 7.51 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
| Smoking Classification Current Smoker | 3 participants | 3 participants | 6 participants |
| Smoking Classification Ex-Smoker | 1 participants | 2 participants | 3 participants |
| Smoking Classification Never Smoked | 2 participants | 1 participants | 3 participants |
| Weight | 61.17 kilogram (kg) STANDARD_DEVIATION 8.373 | 65.40 kilogram (kg) STANDARD_DEVIATION 6.425 | 63.28 kilogram (kg) STANDARD_DEVIATION 7.451 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin
CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in L/hr.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin | 55.84 L/hr | Standard Deviation 9.0078 |
| SYR-322-MET Fed | Apparent Clearance After Extra Vascular Administration (CL/F) for Metformin | 56.75 L/hr | Standard Deviation 9.1099 |
Primary
Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z
CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided AUC (0-inf), expressed in liter/hour (L/hr).
Time frame: 3 hours prior to administration, and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 72 hours after administration
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z | 16.24 L/hr | Standard Deviation 1.6898 |
| SYR-322-MET Fed | Apparent Clearance After Extra Vascular Administration (CL/F) for SYR-322Z | 16.52 L/hr | Standard Deviation 2.2647 |
Primary
Apparent Terminal Elimination Rate Constant (λz) for Metformin
Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Apparent Terminal Elimination Rate Constant (λz) for Metformin | 0.1366 hr^-1 | Standard Deviation 0.028295 |
| SYR-322-MET Fed | Apparent Terminal Elimination Rate Constant (λz) for Metformin | 0.1638 hr^-1 | Standard Deviation 0.02782 |
Primary
Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II
Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 0.02711 hr^-1 | Standard Deviation 0.0039065 |
| SYR-322-MET Fasted | Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 0.06458 hr^-1 | Standard Deviation 0.02346 |
| SYR-322-MET Fed | Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 0.02708 hr^-1 | Standard Deviation 0.0081278 |
| SYR-322-MET Fed | Apparent Terminal Elimination Rate Constant (λz) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 0.06651 hr^-1 | Standard Deviation 0.021985 |
Primary
Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z
Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z | 0.03912 hr^-1 | Standard Deviation 0.0046649 |
| SYR-322-MET Fed | Apparent Terminal Elimination Rate Constant (λz) for SYR-322Z | 0.03673 hr^-1 | Standard Deviation 0.0053316 |
Primary
AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin
AUC (0-48) is measure of area under the curve from time 0 to 48 hours post dose.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin | 9157.3 ng*hr/mL | Standard Deviation 1684.53 |
| SYR-322-MET Fed | AUC (0-48): Area Under the Plasma Concentration-time Curve From Time 0 to 48 Hours Postdose for Metformin | 8991.8 ng*hr/mL | Standard Deviation 1284.97 |
90% CI: [-0.0918, 0.0638]
Primary
AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II
AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II | M-I | 9.49 ng*hr/mL | Standard Deviation 7.746 |
| SYR-322-MET Fasted | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II | M-II | 39.18 ng*hr/mL | Standard Deviation 26.439 |
| SYR-322-MET Fed | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II | M-I | 8.28 ng*hr/mL | Standard Deviation 6.862 |
| SYR-322-MET Fed | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post Dose for SYR-322 Metabolites M-I and M-II | M-II | 37.00 ng*hr/mL | Standard Deviation 26.048 |
Primary
AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z)
AUC (0-72) is measure of area under the curve from time 0 to 72 hours post dose.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z) | 1494.9 nanogram*milliliter per hour (ng*hr/mL) | Standard Deviation 159.42 |
| SYR-322-MET Fed | AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z) | 1472.8 nanogram*milliliter per hour (ng*hr/mL) | Standard Deviation 172.59 |
90% CI: [-0.0592, 0.0264]
Primary
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin
AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin | 9195.3 ng*hr/mL | Standard Deviation 1669.37 |
| SYR-322-MET Fed | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Metformin | 8997.4 ng*hr/mL | Standard Deviation 1289.67 |
90% CI: [-0.095, 0.0591]
Primary
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II
AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 15.86 ng*hr/mL | Standard Deviation 9.168 |
| SYR-322-MET Fasted | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 40.28 ng*hr/mL | Standard Deviation 27.226 |
| SYR-322-MET Fed | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 14.53 ng*hr/mL | Standard Deviation 6.369 |
| SYR-322-MET Fed | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 38.01 ng*hr/mL | Standard Deviation 26.671 |
Primary
AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z
AUC (0-inf) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z | 1555.0 ng*hr/mL | Standard Deviation 167.2 |
| SYR-322-MET Fed | AUC (0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for SYR-322Z | 1536.8 ng*hr/mL | Standard Deviation 187.33 |
90% CI: [-0.0598, 0.032]
Primary
AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin
AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin | 9038.8 ng*hr/mL | Standard Deviation 1661.09 |
| SYR-322-MET Fed | AUC (0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Metformin | 8853.8 ng*hr/mL | Standard Deviation 1271.92 |
90% CI: [-0.0934, 0.0605]
Primary
AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II
AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II | M-I | 8.93 ng*hr/mL | Standard Deviation 7.828 |
| SYR-322-MET Fasted | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II | M-II | 38.48 ng*hr/mL | Standard Deviation 26.579 |
| SYR-322-MET Fed | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II | M-I | 7.72 ng*hr/mL | Standard Deviation 6.906 |
| SYR-322-MET Fed | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322 Metabolites M-I and M-II | M-II | 36.00 ng*hr/mL | Standard Deviation 25.861 |
Primary
AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z
AUC (0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC \[0-tlqc\]).
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z | 1494.9 ng*hr/mL | Standard Deviation 159.42 |
| SYR-322-MET Fed | AUC (0-tlqc): Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for SYR-322Z | 1472.8 ng*hr/mL | Standard Deviation 172.59 |
90% CI: [-0.0592, 0.0264]
Primary
CLr: Renal Clearance of Metformin
CLr is a measure of apparent clearance of the drug from the urine.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | CLr: Renal Clearance of Metformin | 27.88 L/hr | Standard Deviation 4.1525 |
| SYR-322-MET Fed | CLr: Renal Clearance of Metformin | 28.34 L/hr | Standard Deviation 6.3364 |
Primary
CLr: Renal Clearance of SYR-322Z
CLr is a measure of apparent clearance of the drug from the urine. The clearance is the rate at which waste substances are cleared from the blood.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | CLr: Renal Clearance of SYR-322Z | 11.96 L/hr | Standard Deviation 1.2071 |
| SYR-322-MET Fed | CLr: Renal Clearance of SYR-322Z | 12.33 L/hr | Standard Deviation 2.2296 |
Primary
Cmax: Maximum Observed Plasma Concentration for Metformin
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Cmax: Maximum Observed Plasma Concentration for Metformin | 1473.3 ng/mL | Standard Deviation 300.19 |
| SYR-322-MET Fed | Cmax: Maximum Observed Plasma Concentration for Metformin | 1251.7 ng/mL | Standard Deviation 164.03 |
90% CI: [-0.2356, -0.068]
Primary
Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II | M-I | 0.42 ng/mL | Standard Deviation 0.295 |
| SYR-322-MET Fasted | Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II | M-II | 4.18 ng/mL | Standard Deviation 3.052 |
| SYR-322-MET Fed | Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II | M-I | 0.40 ng/mL | Standard Deviation 0.319 |
| SYR-322-MET Fed | Cmax: Maximum Observed Plasma Concentration for SYR-322 Metabolites M-I and M-II | M-II | 3.58 ng/mL | Standard Deviation 2.525 |
Primary
Cmax: Maximum Observed Plasma Concentration for SYR-322Z
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Cmax: Maximum Observed Plasma Concentration for SYR-322Z | 154.9 ng/mL | Standard Deviation 38.72 |
| SYR-322-MET Fed | Cmax: Maximum Observed Plasma Concentration for SYR-322Z | 173.4 ng/mL | Standard Deviation 38.45 |
90% CI: [-0.0405, 0.2769]
Primary
Mean Residence Time (MRT) for Metformin
Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Mean Residence Time (MRT) for Metformin | 6.213 hr | Standard Deviation 0.88315 |
| SYR-322-MET Fed | Mean Residence Time (MRT) for Metformin | 6.097 hr | Standard Deviation 0.63435 |
Primary
Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II
Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). AUMC (0-inf) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 39.87 hr | Standard Deviation 6.1272 |
| SYR-322-MET Fasted | Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 13.93 hr | Standard Deviation 2.2797 |
| SYR-322-MET Fed | Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 49.97 hr | Standard Deviation 38.556 |
| SYR-322-MET Fed | Mean Residence Time (MRT) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 13.81 hr | Standard Deviation 2.1894 |
Primary
Mean Residence Time (MRT) for SYR-322Z
Mean residence time (MRT) calculated as area under the first moment plasma concentration-time curve (AUMC \[0-inf\]) divided by AUC (0-inf). (AUMC \[0-inf\]) is the area under the first moment plasma concentration-time curve from time 0 to infinity.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Mean Residence Time (MRT) for SYR-322Z | 18.06 hr | Standard Deviation 1.4216 |
| SYR-322-MET Fed | Mean Residence Time (MRT) for SYR-322Z | 17.72 hr | Standard Deviation 2.1696 |
Primary
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin
MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: Subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin | 5.697 hr | Standard Deviation 0.75798 |
| SYR-322-MET Fed | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for Metformin | 5.697 hr | Standard Deviation 0.58215 |
Primary
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II
MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II | M-I (n= 11, 11) | 17.95 hr | Standard Deviation 6.3662 |
| SYR-322-MET Fasted | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II | M-II (n=12, 12) | 10.88 hr | Standard Deviation 1.6364 |
| SYR-322-MET Fed | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II | M-I (n= 11, 11) | 17.75 hr | Standard Deviation 6.7278 |
| SYR-322-MET Fed | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322 Metabolites M-I and M-II | M-II (n=12, 12) | 10.45 hr | Standard Deviation 1.7285 |
Primary
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z
MRT (0-tlqc) is a measure of the mean residence time from time 0 to time of the last quantifiable concentration (tlqc) calculated as MRT (0-tlqc) =AUMC (0-tlqc)/AUC (0-tlqc). AUMC (0-tlqc) is the area under the first moment plasma concentration-time curve from time 0 to time of the last quantifiable concentration (tlqc), calculated using the linear trapezoidal rule.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z | 14.84 hr | Standard Deviation 1.2056 |
| SYR-322-MET Fed | MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z | 14.17 hr | Standard Deviation 1.1703 |
Primary
Terminal Phase Elimination Half-life (T1/2) for Metformin
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Terminal Phase Elimination Half-life (T1/2) for Metformin | 5.290 hr | Standard Deviation 1.1735 |
| SYR-322-MET Fed | Terminal Phase Elimination Half-life (T1/2) for Metformin | 4.338 hr | Standard Deviation 0.70681 |
Primary
Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 12.43 hr | Standard Deviation 5.4904 |
| SYR-322-MET Fasted | Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 26.09 hr | Standard Deviation 3.9939 |
| SYR-322-MET Fed | Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II | M-I (n = 9, 9) | 31.39 hr | Standard Deviation 22.996 |
| SYR-322-MET Fed | Terminal Phase Elimination Half-life (T1/2) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 11.70 hr | Standard Deviation 4.5855 |
Primary
Terminal Phase Elimination Half-life (T1/2) for SYR-322Z
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Terminal Phase Elimination Half-life (T1/2) for SYR-322Z | 17.94 hr | Standard Deviation 2.0527 |
| SYR-322-MET Fed | Terminal Phase Elimination Half-life (T1/2) for SYR-322Z | 19.24 hr | Standard Deviation 2.8931 |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SYR-322-MET Fasted | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin | 3.000 hr |
| SYR-322-MET Fed | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Metformin | 3.000 hr |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics of each of the SYR-322 metabolites.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II | M-I (n = 11, 11) | 3.000 hr | Full Range 9.168 |
| SYR-322-MET Fasted | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 3.000 hr | Full Range 27.226 |
| SYR-322-MET Fed | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II | M-I (n = 11, 11) | 1.500 hr | Full Range 6.369 |
| SYR-322-MET Fed | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322 Metabolites M-I and M-II | M-II (n = 12, 12) | 2.500 hr | Full Range 26.671 |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z
Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SYR-322-MET Fasted | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z | 3.000 hour (hr) |
| SYR-322-MET Fed | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for SYR-322Z | 1.00 hour (hr) |
Primary
Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose
Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Time frame: 0 to 24 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose | 50.078 percentage of dose | Standard Deviation 7.5995 |
| SYR-322-MET Fed | Urinary Excretion Ratio of Metformin From 0 to 24 Hours Postdose | 49.923 percentage of dose | Standard Deviation 7.5189 |
Primary
Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose
Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Time frame: 0 to 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose | 50.626 percentage of dose | Standard Deviation 7.6377 |
| SYR-322-MET Fed | Urinary Excretion Ratio of Metformin From 0 to 48 Hours Postdose | 50.067 percentage of dose | Standard Deviation 7.6636 |
Primary
Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose
Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Time frame: 0 to 12 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose | 45.143 percentage of dose | Standard Deviation 7.7692 |
| SYR-322-MET Fed | Urinary Excretion Ratio of Metformin From Time 0 to 12 Hours Postdose | 44.809 percentage of dose | Standard Deviation 7.4874 |
Primary
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose
Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 12 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose | M-I | 0.235 percentage of dose | Standard Deviation 0.1393 |
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose | M-II | 1.202 percentage of dose | Standard Deviation 0.806 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose | M-I | 0.234 percentage of dose | Standard Deviation 0.1719 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose | M-II | 1.145 percentage of dose | Standard Deviation 0.7826 |
Primary
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose
Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 24 hours post dose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose | M-I | 0.394 percentage of dose | Standard Deviation 0.2386 |
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose | M-II | 1.562 percentage of dose | Standard Deviation 1.0106 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose | M-I | 0.363 percentage of dose | Standard Deviation 0.2482 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 24 Hours Postdose | M-II | 1.502 percentage of dose | Standard Deviation 0.9879 |
Primary
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose
Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose | M-I | 0.535 percentage of dose | Standard Deviation 0.3441 |
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose | M-II | 1.788 percentage of dose | Standard Deviation 1.1384 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose | M-I | 0.495 percentage of dose | Standard Deviation 0.3352 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 48 Hours Postdose | M-II | 1.732 percentage of dose | Standard Deviation 1.1284 |
Primary
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose
Cumulative urinary excretion ratio of SYR-322 metabolites M-I and M-II was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose | M-I | 0.588 percentage of dose | Standard Deviation 0.3884 |
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose | M-II | 1.853 percentage of dose | Standard Deviation 1.1929 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose | M-I | 0.536 percentage of dose | Standard Deviation 0.3816 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 72 Hours Postdose | M-II | 1.796 percentage of dose | Standard Deviation 1.1696 |
Primary
Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose
Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 12 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose | 42.609 percentage of dose | Standard Deviation 4.9985 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322Z From 0 to 12 Hours Postdose | 45.028 percentage of dose | Standard Deviation 6.9388 |
Primary
Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose
Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 24 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose | 58.618 percentage of dose | Standard Deviation 4.0606 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322Z From 0 to 24 Hours Postdose | 59.886 percentage of dose | Standard Deviation 6.5474 |
Primary
Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose
Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 48 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose | 70.200 percentage of dose | Standard Deviation 3.8051 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322Z From 0 to 48 Hours Postdose | 71.148 percentage of dose | Standard Deviation 6.4985 |
Primary
Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose
Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
Time frame: 0 to 72 hours postdose
Population: Pharmacokinetic set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacokinetics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose | 73.728 percentage of dose | Standard Deviation 3.914 |
| SYR-322-MET Fed | Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose | 74.547 percentage of dose | Standard Deviation 6.4048 |
Secondary
AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours
Area under the inhibition rate of plasma DPP-4 activity-time curve from time 0 to 24 hours was determined from the inhibition-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
Population: Pharmacodynamic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacodynamics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours | 2114.62 percentage of inhibition*hour | Standard Deviation 30.355 |
| SYR-322-MET Fed | AUC (0-24): Area Under the Inhibition Rate of Plasma DPP-4 Activity-time Curve From Time 0 to 24 Hours | 2100.74 percentage of inhibition*hour | Standard Deviation 27.297 |
Secondary
DPP-4 Activity
DPP-4 activity was assessed from the plasma samples collected from the participants.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
Population: Pharmacodynamic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacodynamics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | DPP-4 Activity | 8 hours | 0.6422 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.09457 |
| SYR-322-MET Fasted | DPP-4 Activity | Predose | 7.8167 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.85551 |
| SYR-322-MET Fasted | DPP-4 Activity | 0.25 hour | 2.5833 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 2.37291 |
| SYR-322-MET Fasted | DPP-4 Activity | 0.5 hour | 1.1944 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 1.641 |
| SYR-322-MET Fasted | DPP-4 Activity | 1 Hour | 0.7122 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.39573 |
| SYR-322-MET Fasted | DPP-4 Activity | 1.5 Hour | 0.6366 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.19955 |
| SYR-322-MET Fasted | DPP-4 Activity | 2 hours | 0.5003 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.17621 |
| SYR-322-MET Fasted | DPP-4 Activity | 3 hours | 0.3575 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.14924 |
| SYR-322-MET Fasted | DPP-4 Activity | 4 hours | 0.3977 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.09285 |
| SYR-322-MET Fasted | DPP-4 Activity | 6 hours | 0.5423 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.07347 |
| SYR-322-MET Fasted | DPP-4 Activity | 24 hours | 1.4275 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.22071 |
| SYR-322-MET Fed | DPP-4 Activity | 24 hours | 1.4550 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.24055 |
| SYR-322-MET Fed | DPP-4 Activity | 2 hours | 0.3475 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.05993 |
| SYR-322-MET Fed | DPP-4 Activity | Predose | 7.8492 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.99173 |
| SYR-322-MET Fed | DPP-4 Activity | 6 hours | 0.6196 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.08548 |
| SYR-322-MET Fed | DPP-4 Activity | 0.25 hour | 3.4518 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 2.8639 |
| SYR-322-MET Fed | DPP-4 Activity | 3 hours | 0.4128 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.06132 |
| SYR-322-MET Fed | DPP-4 Activity | 0.5 hour | 0.7823 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.66267 |
| SYR-322-MET Fed | DPP-4 Activity | 8 hours | 0.7425 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.11652 |
| SYR-322-MET Fed | DPP-4 Activity | 1 Hour | 0.3737 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.21081 |
| SYR-322-MET Fed | DPP-4 Activity | 4 hours | 0.4873 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.08441 |
| SYR-322-MET Fed | DPP-4 Activity | 1.5 Hour | 0.3312 nanomole/minute/milliliter (nmoL/min/mL) | Standard Deviation 0.07085 |
Secondary
Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity
Maximum inhibition rate of plasma DPP-4 activity was determined from the inhibition-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
Population: Pharmacodynamic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacodynamics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SYR-322-MET Fasted | Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity | 96.10 percentage of inhibition | Standard Deviation 1.022 |
| SYR-322-MET Fed | Emax: Maximum Inhibition Rate of Plasma DPP-4 Activity | 96.33 percentage of inhibition | Standard Deviation 0.779 |
Secondary
Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity
DPP-4 activity and inhibition rate of DPP-4 activity was assessed from the plasma samples collected from the participants. Inhibition of DPP-4 enzyme was used to determine the antihyperglycemic activity of the investigational product.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
Population: Pharmacodynamic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacodynamics.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 1 hour | 91.05 percentage of inhibition | Standard Deviation 4.07 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 3 hour | 95.52 percentage of inhibition | Standard Deviation 1.528 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 0.5 hour | 85.65 percentage of inhibition | Standard Deviation 17.721 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 4 hour | 94.88 percentage of inhibition | Standard Deviation 1.216 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 1.5 hour | 91.85 percentage of inhibition | Standard Deviation 2.342 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 6 hour | 93.04 percentage of inhibition | Standard Deviation 0.708 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 0.25 hour | 68.00 percentage of inhibition | Standard Deviation 26.599 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 8 hour | 91.78 percentage of inhibition | Standard Deviation 0.89 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 2 hour | 93.63 percentage of inhibition | Standard Deviation 2.028 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 24 hour | 81.74 percentage of inhibition | Standard Deviation 2.235 |
| SYR-322-MET Fasted | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | Predose | 0.00 percentage of inhibition | Standard Deviation 0 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 24 hour | 81.38 percentage of inhibition | Standard Deviation 2.614 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | Predose | 0.00 percentage of inhibition | Standard Deviation 0 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 0.25 hour | 57.99 percentage of inhibition | Standard Deviation 32.209 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 0.5 hour | 90.31 percentage of inhibition | Standard Deviation 7.533 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 1 hour | 95.27 percentage of inhibition | Standard Deviation 2.371 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 1.5 hour | 95.79 percentage of inhibition | Standard Deviation 0.71 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 2 hour | 95.58 percentage of inhibition | Standard Deviation 0.542 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 3 hour | 94.71 percentage of inhibition | Standard Deviation 0.611 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 4 hour | 93.78 percentage of inhibition | Standard Deviation 0.877 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 6 hour | 92.06 percentage of inhibition | Standard Deviation 0.88 |
| SYR-322-MET Fed | Inhibition Rate of Dipeptidyl-peptidase-4 (DPP-4) Activity | 8 hour | 90.51 percentage of inhibition | Standard Deviation 1.071 |
Secondary
Number of Participants Reporting 1 or More Treatment-emergent Adverse Events
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: Baseline up to the day of discharge (Day 4) in the second intervention period
Population: Safety analysis set: All participants who receive at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-322-MET Fasted | Number of Participants Reporting 1 or More Treatment-emergent Adverse Events | 0 participants |
| SYR-322-MET Fed | Number of Participants Reporting 1 or More Treatment-emergent Adverse Events | 0 participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Body Weight
Clinically significant change participant's body weight observed at any time point are reported.
Time frame: 3 hours prior to administration (predose), 24 and 72 hours postdose
Population: Safety analysis set: All participants who receive at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-322-MET Fasted | Number of Participants With Clinically Significant Change From Baseline in Body Weight | 0 participants |
| SYR-322-MET Fed | Number of Participants With Clinically Significant Change From Baseline in Body Weight | 0 participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs included body temperature (infra-axillary), supine blood pressure resting more than 5 minutes (systolic and diastolic \[Millimeters of mercury\]), respiratory rate and pulse (beats per minute). Clinically significant change in vital signs observed at any time point are reported.
Time frame: 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose
Population: Safety analysis set: All participants who receive at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-322-MET Fasted | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
| SYR-322-MET Fed | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
Secondary
Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs)
Laboratory assessments included hematology, serum chemistry and urinalysis. Any laboratory-related TEAE reported at any time point were reported in this measure.
Time frame: 3 hours prior to administration (predose), 24 and 72 hours postdose
Population: Safety analysis set: All participants who receive at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-322-MET Fasted | Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs) | 0 participants |
| SYR-322-MET Fed | Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs) | 0 participants |
Secondary
Number of Participants With Significant Change From Baseline in Electrocardiograms
Clinically significant change in electrocardiograms observed at any time point are reported.
Time frame: 3 hours prior to administration (predose) and 2, 24 and 72 hours postdose
Population: Safety analysis set: All participants who receive at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SYR-322-MET Fasted | Number of Participants With Significant Change From Baseline in Electrocardiograms | 0 participants |
| SYR-322-MET Fed | Number of Participants With Significant Change From Baseline in Electrocardiograms | 0 participants |
Secondary
Tmax: Time to Reach Emax
Time to reach Emax for the first time was determined from the inhibition-time curve.
Time frame: 3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose
Population: Pharmacodynamic analysis set: subset of participants who received the investigational product, satisfied the minimum requirements of the protocol with no significant deviations, and were assessable for pharmacodynamics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SYR-322-MET Fasted | Tmax: Time to Reach Emax | 3.000 hour |
| SYR-322-MET Fed | Tmax: Time to Reach Emax | 1.000 hour |