Healthy
Conditions
Keywords
Metformin, Bioavailability, Food effect, Pharmacokinetics
Brief summary
This study will assess the food effect on bioavailability of Metformin/Gliclazide fixed dose combination tablet in fed and fasted state.
Interventions
Participants will receive single oral dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting or fed state.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Ethnicity: Mexicans * Weight between 55 and 95 kilogram (kg) * Body mass index between 18 and 27 kilogram per meter square (kg/m\^2) * Nonsmokers or participants who do not smoke more than 5 cigarettes or 1 pipe a day * Good physical and mental health based on the clinical history and physical examination * All results from blood chemistry, hematology, and urinalysis should be within normal ranges or without clinically significant deviations as per Principal Investigator's judgment * Hematology complete blood count \[CBC\]: hematocrit and hemoglobin must be above the lower limit; upper limit may range up to 15 percent (%) * Liver Function Test range as defined in the protocol * Electrocardiogram (12 leads) without clinically significant pathological signs * All women of childbearing potential must have negative tests for pregnancy at screening, and at day -1 for each treatment period and at end of trial (EOT) * Vital signs (blood pressure and pulse) in supine position within normal ranges or with clinically significant abnormalities as per the Principal Investigator's judgment * All women of childbearing potential who are not pregnant or breastfeeding and who are using a highly effective contraceptive method for at least one month before and following dosing * Negative result for alcohol breath test and urine test for drugs of abuse at screening and at each day -1 of the 2 treatment periods * Negative serology tests for human immunodeficiency virus (HIV1 and HIV2 antibodies), hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV) and venereal disease research laboratory (VDRL) test screening * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Participants who have received any investigational drug within 21 days prior to the study start * Participants who have donated or lost 450 milliliter (mL) or more of blood within 21 days prior to the study start * Participants with history of cardiovascular, renal, liver, metabolic, gastrointestinal, neurological, endocrine, or hematopoietic (any type of anemia) diseases; mental disease, surgery or other organic abnormalities which might affect the study of the investigational drug pharmacokinetics * History of gastrointestinal tract surgery * Participants with history of hypersensitivity to the study drug and/or any formulation's ingredient; history of drug induced anaphylaxis * Participants who take any other drug 30 days before the study drug dose and for which at least seven elimination half-lives had not elapsed * Renal failure or renal impairment assessed by using the Cockcroft-Gault formula * Participant's disagreement or lack of capacity to communicate and cooperate with the Investigator, lack of legal capacity or limited legal capacity which prevent him/her from continuing in the study * Refusal of the high-fat diet which is necessary to assess the food effect. Considerable deviations to the diet's normal nutritional patterns * Participants who have smoked tobacco, having drunk alcohol, or xanthines containing beverages or food above 600 mg of caffeine a day those who have had grilled food within 24 h prior to the drug dosing * Intake of grapefruit, orange, cranberries or their juices within 14 days prior to the drug's dosing and throughout the study * Legal inability or limited legal capacity * Incarcerated participants * Participants who have been exposed to agents known as liver enzyme systems' inducers or inhibitors, or who have taken potentially toxic drugs within 30 days prior to the study * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | AUC (0-t) is defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t) |
| Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | Cmax is defined as the maximum observed plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | CL/f is defined as apparent total clearance of the drug from plasma after oral administration. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | Tmax is defined as the time to reach maximum plasma concentration. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Day 39 | Adverse event(AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Elimination Half Life (t1/2) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | Elimination Half Life (t1/2) is defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. |
| Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide | Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose | Vz/f is defined as apparent volume of distribution during terminal phase after non-intravenous administration |
Countries
Mexico
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed) Participants received single dose of Metformin 1000 milligram (mg) and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 2. Each treatment period was separated by a 14-day wash-out period. | 10 |
| Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted) Participants received single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fed state in treatment period 1 followed by single dose of Metformin 1000 mg and Gliclazide 30 mg fixed combination tablet in fasting state in treatment period 2. Each treatment period will be separated by a 14-day wash-out period. | 11 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Metformin-Gliclazide (Fasted), Then Metformin-Gliclazide (Fed) | Metformin-Gliclazide (Fed), Then Metformin-Gliclazide (Fasted) | Total |
|---|---|---|---|
| Age, Continuous | 37.2 Years STANDARD_DEVIATION 10.9 | 32.5 Years STANDARD_DEVIATION 8 | 34.7 Years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 11 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 8 / 21 | 7 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide
AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf).
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: The Pharmacokinetics (PK) analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide | Metformin | 4974.2507 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 1599.329 |
| Metformin-Gliclazide (Fasted) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide | Gliclazide | 21192.1682 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 9220.3044 |
| Metformin-Gliclazide (Fed) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide | Metformin | 8556.7752 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2544.6658 |
| Metformin-Gliclazide (Fed) | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin and Gliclazide | Gliclazide | 21815.4021 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 8369.0107 |
Comparison: Statistical Analysis for Metformin90% CI: [153.779, 200.6664]
Comparison: Statistical Analysis for Gliclazide90% CI: [97.766, 111.606]
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide
AUC (0-t) is defined as the area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t)
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide | Metformin | 4722.4546 ng*h/mL | Standard Deviation 1598.1082 |
| Metformin-Gliclazide (Fasted) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide | Gliclazide | 20348.8381 ng*h/mL | Standard Deviation 9154.5509 |
| Metformin-Gliclazide (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide | Metformin | 8298.5628 ng*h/mL | Standard Deviation 2422.9059 |
| Metformin-Gliclazide (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin and Gliclazide | Gliclazide | 20997.1704 ng*h/mL | Standard Deviation 8244.2743 |
Comparison: Statistical Analysis for Metformin90% CI: [157.0135, 208.1287]
Comparison: Statistical Analysis for Gliclazide90% CI: [98.0047, 112.6699]
Primary
Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide
Cmax is defined as the maximum observed plasma concentration.
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide | Metformin | 717.5017 ng/mL | Standard Deviation 304.8105 |
| Metformin-Gliclazide (Fasted) | Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide | Gliclazide | 968.0305 ng/mL | Standard Deviation 261.8362 |
| Metformin-Gliclazide (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide | Metformin | 870.7288 ng/mL | Standard Deviation 272.6886 |
| Metformin-Gliclazide (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin and Gliclazide | Gliclazide | 1013.9753 ng/mL | Standard Deviation 243.1601 |
Comparison: Statistical Analysis for Metformin90% CI: [110.2732, 148.0612]
Comparison: Statistical Analysis for Gliclazide90% CI: [94.5723, 117.5081]
Secondary
Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma
CL/f is defined as apparent total clearance of the drug from plasma after oral administration.
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: The PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma | Metformin | 226.79 Liters | Standard Deviation 88.58 |
| Metformin-Gliclazide (Fasted) | Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma | Glilclazide | 1.63 Liters | Standard Deviation 0.57 |
| Metformin-Gliclazide (Fed) | Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma | Metformin | 125.93 Liters | Standard Deviation 33.92 |
| Metformin-Gliclazide (Fed) | Apparent Total Body Clearance (CL/f) of Metformin and Gliclazide From Plasma | Glilclazide | 1.55 Liters | Standard Deviation 0.52 |
Secondary
Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide
Vz/f is defined as apparent volume of distribution during terminal phase after non-intravenous administration
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: The PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide | Metformin | 2003389.9474 Milliliter (mL) | Standard Deviation 1157828.4547 |
| Metformin-Gliclazide (Fasted) | Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide | Gliclazide | 35189.3864 Milliliter (mL) | Standard Deviation 8855.9499 |
| Metformin-Gliclazide (Fed) | Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide | Metformin | 1200933.2647 Milliliter (mL) | Standard Deviation 949837.2019 |
| Metformin-Gliclazide (Fed) | Apparent Volume of Distribution (Vz/f) of Metformin and Gliclazide | Gliclazide | 33813.7843 Milliliter (mL) | Standard Deviation 6970.7706 |
Secondary
Elimination Half Life (t1/2) of Metformin and Gliclazide
Elimination Half Life (t1/2) is defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: The PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Elimination Half Life (t1/2) of Metformin and Gliclazide | Metformin | 6.2547 Hours | Standard Deviation 2.9771 |
| Metformin-Gliclazide (Fasted) | Elimination Half Life (t1/2) of Metformin and Gliclazide | Gliclazide | 16.6222 Hours | Standard Deviation 6.2627 |
| Metformin-Gliclazide (Fed) | Elimination Half Life (t1/2) of Metformin and Gliclazide | Metformin | 7.4892 Hours | Standard Deviation 8.7276 |
| Metformin-Gliclazide (Fed) | Elimination Half Life (t1/2) of Metformin and Gliclazide | Gliclazide | 17.1044 Hours | Standard Deviation 7.5 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Adverse event(AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event(SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Day 39
Population: The safety population included all participants who received at least 1 dose of the study treatment in either treatment period 1 or treatment period 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 8 Participants |
| Metformin-Gliclazide (Fasted) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 0 Participants |
| Metformin-Gliclazide (Fed) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse Events | 7 Participants |
| Metformin-Gliclazide (Fed) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious Adverse Events (SAEs) | 0 Participants |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide
Tmax is defined as the time to reach maximum plasma concentration.
Time frame: Pre-dose, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0, 16.0, 24.0, 28.0, 32.0, 48.0, 72.0, 96.0, 120.0, 144.0 and 168.0 hour post-dose
Population: The PK analysis set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect the comparability of PK results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin-Gliclazide (Fasted) | Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide | Metformin | 3.6698 Hours | Standard Deviation 0.66 |
| Metformin-Gliclazide (Fasted) | Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide | Gliclazide | 6.5254 Hours | Standard Deviation 1.7474 |
| Metformin-Gliclazide (Fed) | Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide | Metformin | 7.2389 Hours | Standard Deviation 0.7693 |
| Metformin-Gliclazide (Fed) | Time to Reach Maximum Plasma Concentration (Tmax) of Metformin and Gliclazide | Gliclazide | 8.5238 Hours | Standard Deviation 2.1822 |