An Assessment of Pharmacokinetic Gemigliptin and Metformin Interactions in Healthy Mexican Volunteers

Study Overview
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Brief Summary
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This is an open, randomized (randomization ratio: 1:1), multiple dose, three way, three period cross over study to assess the potential for drug drug interactions between gemigliptin (a DPP-IV inhibitor mainly metabolized by CYP3A4) and metformin in a sample of healthy Mexican volunteers, aimed to determine whether the observed lack of drug-drug interactions between gemigliptin and metformin in the Korean population is reproducible in an ethnically different population characterized by a significant difference in the frequency of CYP3A4 polymorphisms associated with decreased enzymatic activity, such as CYP3A4*1b, in comparison with Asian populations.

Detailed Description
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Consenting, eligible healthy adult subjects sequentially received either gemigliptin 50 mg q.d., metformin 1000 mg twice a day or gemigliptin 50 mg q.d. plus metformin 1000 mg twice a day during 3 consecutive 7 day treatment periods separated by two 5-day washout intervals, in accordance with a randomly assigned treatment sequence. Starting on the sixth treatment period day, participating subjects underwent safety assessments and repeated (24 hour) blood and urine sampling for pharmacokinetic analysis. All subjects attended to a post-study visit for final safety assessments within 8 days of study completion or early withdrawal. Urine and plasma samples where processed to determine gemigliptin and metformin concentrations using validated analytical methods and pharmacokinetic profiles of both gemigliptin and metformin were obtained using a non-compartmental method; both the rate and degree of gemigliptin and metformin absorption resulting from their concomitant administration relative to the administration of each drug alone were assessed in search of potential pharmacokinetic interactions, Finally, a post hoc assessment of the degree and rate of the absorption of gemigliptin in the study population relative to those of a group of Korean subjects participating in phase I, repeated dose gemigliptin studies was conducted.

Official Title
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A Randomized, Open-label, Multiple Dosing, Three-way Crossover Clinical Trial to Investigate the Pharmacokinetic Drug-drug Interaction of Gemigliptin and Metformin After Oral Administration in Healthy Mexican Male Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Gemigliptin
* Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects at age between 20 and 45 at the screening test Subjects with a body weight of 55kg or more but less than 90kg and a Body Mass Index (BMI) of between 18.0 or more but less than 27.0 BMI (kg/m2) = Weight (kg) / {Height (m)}2 Subjects who show the blood glucose level within the range of 70-125 mg/dL at the fasting plasma glucose (FPG) test conducted at screening Subjects who fully understand this clinical trial after hearing a detailed explanation about it, make a decision to participate in it by his/her own free will, and sign an informed consent form to comply with the precautions Exclusion Criteria: Subjects who have a present condition or past history of any disease involving liver, kidney, nervous system, immune system, respiratory system, or endocrine system, hematologic and oncologic disease, cardiovascular disease, or psychiatric disorder (mood disorder, obsessive-compulsive disorder, etc.) (including subjects carrying hepatitis virus in case of liver disease) Subjects with a past history of a gastrointestinal system disease (Crohn's disease, ulcer, acute or chronic pancreatitis, etc.) or a gastrointestinal system surgery (however, subjects with a history of appendectomy or hernioplasty are not excluded) Subjects with a medical history of allergic reaction to drugs (aspirin, antibiotics, etc.) or clinically significant hypersensitivity reaction Subjects who show one of the following results at screening test: Exceeds 1.5 times the upper limit of the normal range of blood AST (SGOT) and ALT (SGPT) The creatinine clearance calculated by Cockcroft-Gault equation is below 80 mL/min. QTc > 450 ms in ECG or clinically significant abnormal rhythm In the vital signs measured in sitting position after a rest for 3 minutes or longer, subjects who showed a systolic blood pressure of ≤ 100 mmHg or ≥ 150 mmHg, or a diastolic blood pressure of ≤ 60 mmHg or ≥ 95 mmHg) Subjects who have a past history of drug abuse or have shown a positive reaction to drugs that are used in abusive manner or cotinine at a urine drug screening Subjects who have taken any ethical drug or an herbal medication within 2 weeks before the date of first administration or have taken any over-the-counter (OTC) drug or vitamin preparation within 1 week (however, they can be included as subjects if considered appropriate at the investigator's discretion judgment) Subject who have already participated in other clinical trials within 2 months before the date of first drug administration Subject who have had whole blood donation within 2 months or component blood donation within 1 month before the date of first drug administration, or transfusion in 1 month before the date of first drug administration Subjects who have been drinking alcohol continuously (more than 21 units/week, 1 unit = 10 g of pure alcohol) or can't refrain from drinking alcohol during the clinical trial period Smokers (however, if the subject stopped smoking more than 3 months before the date of the first drug administration, he/she can be selected as a subject) 12) Subjects who have had grapefruit/ any food containing caffeine within 3 days before the date of the first drug administration

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Open, randomized, multiple dose, three way, three period, cross over, drug-drug interaction, safety and tolerability study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment sequence A<br>Gemigliptin 50 mg q.d. during 7 days, metformin 1000 mg twice a day during 7 days and gemigliptin 50 mg q.d + metformin 1000 mg twice a day during 7 days. | Drug: Gemigliptin<br>* A 7-day treatment period with gemigliptin 50 mg q.d., followed by a 5-day washout period; a 7 day treatment period with metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* Other names: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day;Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* A 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d. followed by a 5-day washout period and a final 7-day treatment period with metformin 1000 mg twice a day<br>* Other names: Metformin;Drug: Metformin<br>* A 7-day treatment period with 1000 mg metformin twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d.+ metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d.<br>* Other names: Gemigliptin;|
| Other: Treatment sequence B<br>Gemigliptin 50 mg q.d + metformin 1000 mg twice a day during 7 days, gemigliptin 50 mg q.d. during 7 days, metformin 1000 mg twice a day during 7 days | Drug: Gemigliptin<br>* A 7-day treatment period with gemigliptin 50 mg q.d., followed by a 5-day washout period; a 7 day treatment period with metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* Other names: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day;Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* A 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d. followed by a 5-day washout period and a final 7-day treatment period with metformin 1000 mg twice a day<br>* Other names: Metformin;Drug: Metformin<br>* A 7-day treatment period with 1000 mg metformin twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d.+ metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d.<br>* Other names: Gemigliptin;|
| Other: Treatment sequence C<br>Metformin 1000 mg twice a day during 7 days, gemigliptin 50 mg q.d + metformin 1000 mg twice a day during 7 days, gemigliptin 50 mg q.d. during 7 days | Drug: Gemigliptin<br>* A 7-day treatment period with gemigliptin 50 mg q.d., followed by a 5-day washout period; a 7 day treatment period with metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* Other names: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day;Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day<br>* A 7-day treatment period with gemigliptin 50 mg q.d. + metformin 1000 mg twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d. followed by a 5-day washout period and a final 7-day treatment period with metformin 1000 mg twice a day<br>* Other names: Metformin;Drug: Metformin<br>* A 7-day treatment period with 1000 mg metformin twice a day followed by a 5-day washout period; a 7-day treatment period with gemigliptin 50 mg q.d.+ metformin 1000 mg twice a day followed by a 5-day washout period and a final 7-day treatment period with gemigliptin 50 mg q.d.<br>* Other names: Gemigliptin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gemigliptin AUCτ,ss Geometric Mean Ratio (and 90%CI) | AUCτ,ss Geometric Mean Ratio for gemigliptin when administered concomitanty with metformin (test) to its administration alone (reference) | At steady state, on the sixth planned treatment day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gemigliptin Cmax,ss Geometric Mean Ratio (and 90%CI) | Cmax,ss Geometric Mean Ratio for gemigliptin when administered concomitanty with metformin (test) to its administration alone (reference) | At steady state, on the sixth planned treatment day | 
| Metformin AUCτ,ss Geometric Mean Ratio (and 90%CI) | AUCτ,ss Geometric Mean Ratio for metformin when administered concomitanty with metformin (test) to its administration alone (reference) | At steady state, on the sixth planned treatment day | 
| Metformin Cmax,ss Geometric Mean Ratio (and 90%CI) | Cmax,ss Geometric Mean Ratio for metformin when administered concomitanty with metformin (test) to its administration alone (reference) | At steady state, on the sixth planned treatment day | 
| Ctrough,ss | Lowest plasma concentration prior to the next dose administration at steady state | At steady state, on the sixth planned treatment day | 
| Aeτ,ss | cumulative amount of drug excreted in the urine during a dosing interval | At steady state, on the sixth planned treatment day | 
| CLss/F | Apparent drug clearance | At steady state, on the sixth planned treatment day | 
| CLR,ss | Renal drug clearance | At steady state, on the sixth planned treatment day | 
| MR | Metabolic ratio | At steady state, on the sixth planned treatment day | 
| Tmax | Time to maximum plasma concentration at steady state | At steady state, on the sixth planned treatment day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, DPP-IV inhibitor, Drug-Drug Interactions, Ethnicity