A Randomized, Open-label, Crossover Study to Determine the Effect of Food on the Pharmacokinetics of Single Oral Dose Administration of a Fixed-Dose Combination of SYR-322 and Metformin Hydrochloride in Healthy Adult Male Subjects
Overview
- Phase
- Phase 3
- Intervention
- SYR-322-MET
- Conditions
- Clinical Pharmacology
- Sponsor
- Takeda
- Enrollment
- 12
- Primary Endpoint
- AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •In the opinion of the investigator or subinvestigator, the subject is capable of understanding and complying with protocol requirements.
- •The subject signs and dates a written, informed consent form prior to the initiation of any study procedures.
- •The subject is a Japanese healthy adult male.
- •The subject is aged 20 to 35 years, inclusive, at the time of informed consent.
- •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
- •The subject has received any investigational compound within 16 weeks (112 days) prior to the start of study drug administration in Period
- •The subject has received SYR-322 or metformin hydrochloride in a previous clinical study or as a therapeutic agent.
- •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.
- •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.
- •The subject has a known hypersensitivity to drugs.
- •The subject has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at screening.
- •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.
- •Subject has taken any excluded medication, supplements, or food products during the time periods listed in the Excluded Medications and Dietary Products table.
- •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.
- •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 \[e.g., cholecystectomy\]).
Arms & Interventions
Fasted dosing followed by fed dosing
Oral administration
Intervention: SYR-322-MET
Fed dosing followed by fasted dosing
Oral administration
Intervention: SYR-322-MET
Outcomes
Primary Outcomes
AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Unchanged SYR-322 (SYR-322Z)
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
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
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
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
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
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
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
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
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
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
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
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.
Mean Residence Time (MRT) for SYR-322Z
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
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.
MRT (0-tlqc): Mean Residence Time From Time 0 to Time of the Last Quantifiable Concentration (Tlqc) for SYR-322Z
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
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 Post Dose for SYR-322 Metabolites M-I and M-II
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
Terminal Phase Elimination Half-life (T1/2) for SYR-322Z
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
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
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
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-322 Metabolites M-I and M-II
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Time Frame: 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
Time Frame: 0 to 24 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 48 Hours Postdose
Time Frame: 0 to 48 hours postdose
Cumulative urinary excretion ratio of unchanged SYR-322 was calculated as the percentage of SYR-322 dose.
CLr: Renal Clearance of SYR-322Z
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
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.
Urinary Excretion Ratio of SYR-322Z From 0 to 72 Hours Postdose
Time Frame: 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 Metformin From Time 0 to 12 Hours Postdose
Time Frame: 0 to 12 hours postdose
Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
Urinary Excretion Ratio of SYR-322 Metabolites M-I and M-II From 0 to 12 Hours Postdose
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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 0 to 24 Hours Postdose
Time Frame: 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
Time Frame: 0 to 48 hours postdose
Cumulative urinary excretion ratio of metformin was calculated as the percentage of metformin dose.
CLr: Renal Clearance of Metformin
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
CLr is a measure of apparent clearance of the drug from the urine.
Secondary Outcomes
- 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(3 hours prior to administration (predose) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours postdose)
- 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)
- 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)
- 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)
- 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)
- 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)
- Number of Participants With Significant Change From Baseline in Electrocardiograms(3 hours prior to administration (predose) and 2, 24 and 72 hours postdose)
- Number of Participants With Laboratory-related Treatment Emergent Adverse Events (TEAEs)(3 hours prior to administration (predose), 24 and 72 hours postdose)
- Number of Participants With Clinically Significant Change From Baseline in Body Weight(3 hours prior to administration (predose), 24 and 72 hours postdose)