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

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Metformin/Gliclazide Fixed Combination
Drug: Metformin
Drug: Gliclazide

Registration Number: NCT03467945

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment Sequence 1	Metformin/Gliclazide Fixed Combination	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.
Treatment Sequence 1	Gliclazide	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.
Treatment Sequence 2	Metformin/Gliclazide Fixed Combination	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.
Treatment Sequence 3	Metformin/Gliclazide Fixed Combination	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.
Treatment Sequence 4	Metformin/Gliclazide Fixed Combination	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.
Treatment Sequence 1	Metformin	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.
Treatment Sequence 2	Gliclazide	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.
Treatment Sequence 2	Metformin	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.
Treatment Sequence 3	Metformin	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.
Treatment Sequence 4	Gliclazide	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.
Treatment Sequence 3	Gliclazide	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.
Treatment Sequence 4	Metformin	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.

Primary Outcome Measures

Name	Time	Method
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 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
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) 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	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	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	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	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).

Secondary Outcome Measures

Name	Time	Method
Apparent Total Body Clearance (CL/f) 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	CL/f was defined as apparent total clearance of the drug from plasma after oral administration.
Apparent Volume of Distribution (Vz/f) 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	Vz/f was defined as apparent volume of distribution during terminal phase after non-intravenous administration.
Apparent Total Body Clearance (CL/f) 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	CL/f was defined as apparent total clearance of the drug from plasma after oral administration.
Apparent Volume of Distribution (Vz/f) 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	Vz/f was defined as apparent volume of distribution during terminal phase after non-intravenous administration.
Elimination Half Life (t1/2) 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	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.
Median Residence Time (MRT) for 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	MRT is the average time that the molecules introduced into the body stays in the body.
Median Residence Time (MRT) for 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	MRT is the average time that the molecules introduced into the body stays in the body.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	Baseline up to Day 72	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.
Elimination Half Life (t1/2) 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	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.