Bioequivalence and Drug - Drug Interaction Study of Metformin/Gliclazide in Healthy Participants

Study Overview
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Brief Summary
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This study investigated the bioequivalence and drug-drug interaction of Metformin/Gliclazide fixed combination tablet compared to co-administration of individual tablets of Metformin and Gliclazide.

Official Title
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Randomized, Open Label, Single Dose, 4 Treatment, 4 Period, Crossover Design (4 x 4) Trial to Evaluate the Bioequivalence and Secondarily Drug - Drug Interaction of Fixed Combination of Metformin Tablets 1000 mg/Gliclazide 30 mg MR, Compared With the Co-administration of Individual Tablets and Individual Administration of Each Single Tablet (Metformin 1000 mg XR and Gliclazide 30 mg MR) in Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Metformin/Gliclazide Fixed Combination
* Drug: Metformin
* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants has given written informed consent before any study-related activities were carried out Ethnic origin: Mexicans Weight between 55 and 95 kilogram (kg) Body mass index between 18.5 and 27 kilogram per meter square (kg/m^2) Not smoking more than 5 cigarettes or 1 cigar or 1 pipe per day (or non smokers) Good physical and mental health status Vital signs (blood pressure and pulse) in supine position within the normal range or showing no clinically relevant deviation as judged by the Investigator Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in particular QTc (Bazett) <450 milliseconds (ms) All values for biochemistry and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator All women of childbearing potential (WOCBP) were not nursing, were not pregnant, and were using highly effective methods of birth control for a period of at least one month before and after dosing 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) Negative screen for alcohol and drugs of abuse at Screening and on each admission Negative screen for Hepatitis B surface (HBs) antigens, Hepatitis C Virus (HCV) antibodies, Hepatitis A Virus (HAV) antibodies and Human Immunodeficiency Virus (HIV) 1 and 2 antibodies Other protocol defined inclusion criteria could apply Exclusion Criteria: Participation in a clinical trial within 90 days prior to first drug administration Participants who have donated more than 500 milliliter (mL) of blood or who have lost significantly (more than 450 mL) blood within 90 days prior to first drug of administration Any surgical or medical condition, constitutes a risk or a contraindication for the participation of the participant in the study or that could interfere with the study objectives, conduct or evaluation History of surgery of the gastrointestinal tract Allergy Receipt of any prescription or non-prescription medication within 2 weeks before the first study drug administration Renal failure or renal dysfunction (creatinine clearance less than [<] 80 mL/minute) as assessed by using the estimated measure with the Cockcroft-Gault formula Known lack of participant compliance or inability to communicate or cooperate with the Investigator Considerable diet deviations from normal nutritional patterns Consumption of large quantities of methylxanthine-containing beverages (more than 600 milligram [mg] caffeine / day: one cup [240 mL] of coffee contains approx. 100 mg of caffeine, one cup of tea approximately 30 mg and one glass of cola approximately 20 mg caffeine) Consumption of grapefruit, orange, cranberry or juices of these fruits, 14 days prior to drug administration and during the study Legal incapacity or limited legal capacity Participants kept in detention Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>Participants received single oral dose of metformin 1000 milligram (mg) and gliclazide 30 mg fixed combination tablet in treatment period 1 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg in treatment period 3 and then a single oral dose of gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. | Drug: Metformin/Gliclazide Fixed Combination<br>* Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4.<br>Drug: Metformin<br>* Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4.<br>Drug: Gliclazide<br>* Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.<br>|
| Experimental: Treatment Sequence 2<br>Participants received concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 1 followed by single oral dose of gliclazide 30 mg in treatment period 2 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 3 and then single oral dose of metformin 1000 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. | Drug: Metformin/Gliclazide Fixed Combination<br>* Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4.<br>Drug: Metformin<br>* Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4.<br>Drug: Gliclazide<br>* Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.<br>|
| Experimental: Treatment Sequence 3<br>Participants received single oral dose of metformin 1000 mg in treatment period 1 followed by single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 2 followed by single oral dose of gliclazide 30 mg in treatment period 3 and then concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 4. Each treatment period was separated by a 14-day wash-out period. | Drug: Metformin/Gliclazide Fixed Combination<br>* Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4.<br>Drug: Metformin<br>* Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4.<br>Drug: Gliclazide<br>* Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.<br>|
| Experimental: Treatment Sequence 4<br>Participants received single oral dose of gliclazide 30 mg in treatment period 1 followed by single oral dose of metformin 1000 mg in treatment period 2 followed by concomitant oral dosing of metformin 1000 mg and gliclazide 30 mg in treatment period 3 and then single oral dose of metformin 1000 mg and gliclazide 30 mg fixed combination tablet in treatment period 4. Each treatment period was separated by a 14-day wash-out period. | Drug: Metformin/Gliclazide Fixed Combination<br>* Participants received single oral dose of Metformin and Gliclazide fixed combination tablet in treatment period 1, 2, 3 or 4.<br>Drug: Metformin<br>* Participants received single oral dose of Metformin tablet in treatment period 1, 2, 3 or 4.<br>Drug: Gliclazide<br>* Participants received single oral dose of Gliclazide tablet in treatment period 1, 2, 3 or 4.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin |  | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Gliclazide |  | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Metformin |  | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Maximum Observed Plasma Concentration (Cmax) of Gliclazide |  | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Metformin | 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). | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of 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). | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apparent Volume of Distribution (Vz/f) of Metformin | Vz/f was defined as apparent volume of distribution during terminal phase after non-intravenous administration. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Apparent Volume of Distribution (Vz/f) of Gliclazide | Vz/f was defined as apparent volume of distribution during terminal phase after non-intravenous administration. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Elimination Half Life (t1/2) of Metformin | Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Elimination Half Life (t1/2) of Gliclazide | Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Apparent Total Body Clearance (CL/f) of Metformin | CL/f was defined as apparent total clearance of the drug from plasma after oral administration. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Apparent Total Body Clearance (CL/f) of Gliclazide | CL/f was defined as apparent total clearance of the drug from plasma after oral administration. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Median Residence Time (MRT) for Metformin | MRT is the average time that the molecules introduced into the body stays in the body. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Median Residence Time (MRT) for Gliclazide | MRT is the average time that the molecules introduced into the body stays in the body. | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 28, 32, 48, 72, 96, 120, 144 and 168 hours post-dose | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. TEAEs included both Serious TEAEs and non-serious TEAEs. | Baseline up to Day 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Gliclazide, Bioequivalence, Drug-drug Interaction, Pharmacokinetics