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

NCT02276274 | Completed Phase 3 Results

• 3 other identifiers: SYR-322-MET/CPH-002U1111-1157-8500JapicCTI-142584
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Clinical Pharmacology

Outcome Measures

Primary Outcomes (42)

• 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.

  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): 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 \[0-tlqc\]).

  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

• 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.

  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) for SYR-322Z

  Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  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): 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.

  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

• 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.

  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) 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.

  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

• 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).

  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

• 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.

  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): 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.

  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): 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.

  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): 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 \[0-tlqc\]).

  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): 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.

  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

• 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.

  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) for SYR-322 Metabolites M-I and M-II

  Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  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): 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.

  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

• 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.

  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) 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.

  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) 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.

  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 (0-48): 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.

  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): 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 \[0-tlqc\]).

  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): 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.

  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

• 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.

  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) for Metformin

  Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.

  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): 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.

  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

• 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.

  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) for Metformin

  Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

  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

• 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.

  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) 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.

  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

• 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.

  0 to 12 hours postdose

• 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.

  0 to 24 hours postdose

• 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.

  0 to 48 hours postdose

• 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.

  0 to 72 hours postdose

• 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.

  0 to 12 hours postdose

• 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.

  0 to 24 hours post dose

• 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.

  0 to 48 hours postdose

• 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.

  0 to 72 hours postdose

• 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.

  0 to 12 hours postdose

• 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.

  0 to 24 hours postdose

• 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.

  0 to 48 hours postdose

• 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.

  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: Renal Clearance of Metformin

  CLr is a measure of apparent clearance of the drug from the urine.

  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

Secondary Outcomes (10)

• 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

Study Arms (2)

Fasted dosing followed by fed dosing

EXPERIMENTAL

Oral administration

Drug: SYR-322-MET

Fed dosing followed by fasted dosing

EXPERIMENTAL

Oral administration

Drug: SYR-322-MET

Interventions

SYR-322-MET DRUG

Oral administration of SYR-322-MET

Fasted dosing followed by fed dosing; Fed dosing followed by fasted dosing

Eligibility Criteria

• Age: 20 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• The subject has received any investigational compound within 16 weeks (112 days) prior to the start of study drug administration in Period 1.
• 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 \[e.g., cholecystectomy\]).
• The subject has a history of cancer.
• 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.
• The subject has poor peripheral venous access.
• 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.
• 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.

Sponsors & Collaborators

• Takeda: lead

Study Sites (1)

Unknown Facility

Fukuoka, Fukuoka, Japan

Location

Results Point of Contact

• Title: Study Director
• Organization: Takeda (Note: This product was divested to Teijin Pharma Limited in 2023)

TrialDisclosures@takeda.com

+1-877-825-3327

Study Officials

• General Manager

  Takeda Pharmaceutical Company Limited (Japan)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2014
• First Posted: October 28, 2014
• Study Start: June 1, 2014
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: September 21, 2023
• Results First Posted: June 29, 2015

Record last verified: 2023-08

Locations

JP (1)