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

NCT ID: NCT03310749

Last Updated: 2017-10-16

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

34 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-01-15

Study Completion Date

2016-05-03

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.

Conditions

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Diabetes Mellitus, Type 2

Keywords

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Type 2 Diabetes Mellitus DPP-IV inhibitor Drug-Drug Interactions Ethnicity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Open, randomized, multiple dose, three way, three period, cross over, drug-drug interaction, safety and tolerability study
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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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.

Group Type OTHER

Gemigliptin

Intervention Type DRUG

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

Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day

Intervention Type DRUG

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

Metformin

Intervention Type DRUG

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.

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

Group Type OTHER

Gemigliptin

Intervention Type DRUG

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

Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day

Intervention Type DRUG

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

Metformin

Intervention Type DRUG

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.

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

Group Type OTHER

Gemigliptin

Intervention Type DRUG

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

Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day

Intervention Type DRUG

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

Metformin

Intervention Type DRUG

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.

Interventions

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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

Intervention Type 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

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Metformin Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day Gemigliptin Metformin Gemigliptin 50 mg q.d. + metformin 1000 mg twice a day Gemigliptin

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
Minimum Eligible Age

20 Years

Maximum Eligible Age

45 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

Yes

Sponsors

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Universidad Nacional Autonoma de Mexico

OTHER

Sponsor Role collaborator

LG Chem

INDUSTRY

Sponsor Role collaborator

Stendhal Americas, S.A.

INDUSTRY

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Ignacio Conde-Carmona, MD

Role: STUDY_CHAIR

Específicos Stendhal S.A. de C.V.

Locations

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Unidad de Farmacología Clínica de la Facultad de Medicina de la Universidad Nacional Autónoma de México

Nezahualcóyotl, State of Mexico, Mexico

Site Status

Countries

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Mexico

References

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Kim SH, Jung E, Yoon MK, Kwon OH, Hwang DM, Kim DW, Kim J, Lee SM, Yim HJ. Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo. Eur J Pharmacol. 2016 Oct 5;788:54-64. doi: 10.1016/j.ejphar.2016.06.016. Epub 2016 Jun 11.

Reference Type BACKGROUND
PMID: 27298192 (View on PubMed)

Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ. Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study. Clin Ther. 2008 Oct;30(10):1817-30. doi: 10.1016/j.clinthera.2008.10.013.

Reference Type BACKGROUND
PMID: 19014837 (View on PubMed)

Lim KS, Cho JY, Kim BH, Kim JR, Kim HS, Kim DK, Kim SH, Yim HJ, Lee SH, Shin SG, Jang IJ, Yu KS. Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers. Br J Clin Pharmacol. 2009 Dec;68(6):883-90. doi: 10.1111/j.1365-2125.2009.03376.x.

Reference Type BACKGROUND
PMID: 20002082 (View on PubMed)

Kim N, Patrick L, Mair S, Stevens L, Ford G, Birks V, Lee SH. Absorption, metabolism and excretion of [14C]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Xenobiotica. 2014 Jun;44(6):522-30. doi: 10.3109/00498254.2013.865856. Epub 2013 Dec 4.

Reference Type BACKGROUND
PMID: 24304170 (View on PubMed)

Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 Dec;116(3):496-526. doi: 10.1016/j.pharmthera.2007.09.004. Epub 2007 Oct 9.

Reference Type BACKGROUND
PMID: 18001838 (View on PubMed)

Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013 Apr;138(1):103-41. doi: 10.1016/j.pharmthera.2012.12.007. Epub 2013 Jan 16.

Reference Type BACKGROUND
PMID: 23333322 (View on PubMed)

Reyes-Hernandez OD, Lares-Asseff I, Sosa-Macias M, Vega L, Albores A, Elizondo G. A comparative study of CYP3A4 polymorphisms in Mexican Amerindian and Mestizo populations. Pharmacology. 2008;81(2):97-103. doi: 10.1159/000109983. Epub 2007 Oct 19.

Reference Type BACKGROUND
PMID: 17952011 (View on PubMed)

Shin D, Cho YM, Lee S, Lim KS, Kim JA, Ahn JY, Cho JY, Lee H, Jang IJ, Yu KS. Pharmacokinetic and pharmacodynamic interaction between gemigliptin and metformin in healthy subjects. Clin Drug Investig. 2014 Jun;34(6):383-93. doi: 10.1007/s40261-014-0184-3.

Reference Type BACKGROUND
PMID: 24627290 (View on PubMed)

Conde-Carmona I, Garcia-Medina S, Jimenez-Vargas JM, Martinez-Munoz A, Lee SH. Pharmacokinetic Interactions Between Gemigliptin and Metformin, and Potential Differences in the Pharmacokinetic Profile of Gemigliptin Between the Mexican and Korean Populations: A Randomized, Open-label Study in Healthy Mexican Volunteers. Clin Ther. 2018 Oct;40(10):1729-1740. doi: 10.1016/j.clinthera.2018.08.015. Epub 2018 Sep 22.

Reference Type DERIVED
PMID: 30249366 (View on PubMed)

Other Identifiers

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LG/STDHL-DPCL009bis

Identifier Type: -

Identifier Source: org_study_id