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

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ClinicalTrials.gov Identifier: NCT03310749
Recruitment Status : Completed
First Posted : October 16, 2017
Last Update Posted : October 16, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Drug: Gemigliptin Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day Drug: Metformin Phase 1

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 Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Open, randomized, multiple dose, three way, three period, cross over, drug-drug interaction, safety and tolerability study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 15, 2016
Primary Completion Date : May 3, 2016
Study Completion Date : May 3, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Treatment sequence A
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
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
Other Names:
  • Metformin
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
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
Other Names:
  • Gemigliptin
  • Metformin
Drug: Metformin
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.
Other Names:
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
  • Gemigliptin
Treatment sequence B
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
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
Other Names:
  • Metformin
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
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
Other Names:
  • Gemigliptin
  • Metformin
Drug: Metformin
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.
Other Names:
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
  • Gemigliptin
Treatment sequence C
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
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
Other Names:
  • Metformin
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
Drug: Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
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
Other Names:
  • Gemigliptin
  • Metformin
Drug: Metformin
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.
Other Names:
  • Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day
  • Gemigliptin


Outcome Measures

Primary Outcome Measures :
  1. Gemigliptin AUCτ,ss Geometric Mean Ratio (and 90%CI) [ Time Frame: 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 :
  1. Gemigliptin Cmax,ss Geometric Mean Ratio (and 90%CI) [ Time Frame: 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)

  2. Metformin AUCτ,ss Geometric Mean Ratio (and 90%CI) [ Time Frame: 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)

  3. Metformin Cmax,ss Geometric Mean Ratio (and 90%CI) [ Time Frame: 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)

  4. Ctrough,ss [ Time Frame: At steady state, on the sixth planned treatment day ]
    Lowest plasma concentration prior to the next dose administration at steady state

  5. Aeτ,ss [ Time Frame: At steady state, on the sixth planned treatment day ]
    cumulative amount of drug excreted in the urine during a dosing interval

  6. CLss/F [ Time Frame: At steady state, on the sixth planned treatment day ]
    Apparent drug clearance

  7. CLR,ss [ Time Frame: At steady state, on the sixth planned treatment day ]
    Renal drug clearance

  8. MR [ Time Frame: At steady state, on the sixth planned treatment day ]
    Metabolic ratio

  9. Tmax [ Time Frame: At steady state, on the sixth planned treatment day ]
    Time to maximum plasma concentration at steady state


Other Outcome Measures:
  1. Incidence of treatment-emergent adverse events [ Time Frame: From the first pre-treatment admission date, trough the 39 days required for completion of the planned treatment/sampling and washout periods up to and including the post-study safety visit, conducted at study day 44 ]
    Incidence of adverse events occuring during the exposure to the study medications


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03310749


Locations
Mexico
Unidad de Farmacología Clínica de la Facultad de Medicina de la Universidad Nacional Autónoma de México
Nezahualcóyotl, Estado de México, Mexico, 57740
Sponsors and Collaborators
Stendhal Americas, S.A.
Universidad Nacional Autonoma de Mexico
LG Chem
Investigators
Study Chair: Ignacio Conde-Carmona, MD Específicos Stendhal S.A. de C.V.
More Information

Publications:

Responsible Party: Stendhal Americas, S.A.
ClinicalTrials.gov Identifier: NCT03310749     History of Changes
Other Study ID Numbers: LG/STDHL-DPCL009bis
First Posted: October 16, 2017    Key Record Dates
Last Update Posted: October 16, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No formal plan has been established since at the time the study was conducted no consent was obtained from the subjects to share their individual data for research purposes different from those specifically defined in the study protocol

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Stendhal Americas, S.A.:
Type 2 Diabetes Mellitus
DPP-IV inhibitor
Drug-Drug Interactions
Ethnicity

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs