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

Phase 1

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: Gemigliptin; Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day; Drug: Metformin

• Registration Number: NCT03310749
• Lead Sponsor: Stendhal Americas, S.A.

Brief Summary

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

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.

Study Timeline

• Study Start: 2016-01-15
• Primary Completion: 2016-05-03
• Study Completion: 2016-05-03
• Study First Submitted: 2017-09-13
• Status Verified: 2017-10
• Study First Submitted QC: 2017-10-13
• Last Update Submitted: 2017-10-13
• Study First Posted: 2017-10-16
• Last Update Posted: 2017-10-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 34

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment sequence A	Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day	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.
Treatment sequence B	Gemigliptin	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
Treatment sequence C	Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day	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
Treatment sequence B	Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day	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
Treatment sequence A	Gemigliptin	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.
Treatment sequence A	Metformin	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.
Treatment sequence B	Metformin	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
Treatment sequence C	Gemigliptin	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
Treatment sequence C	Metformin	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

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Unidad de Farmacología Clínica de la Facultad de Medicina de la Universidad Nacional Autónoma de México; 🇲🇽 Nezahualcóyotl, Estado de México, Mexico