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

Diabetes Mellitus, Type 2 Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03310749
• Other study ID #: LG/STDHL-DPCL009bis
• Status: Completed
• Phase: Phase 1
• First received: September 13, 2017
• Last updated: October 13, 2017
• Start date: January 15, 2016
• Est. completion date: May 3, 2016

Study information

• Verified date: October 2017
• Source: Stendhal Americas, S.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: May 3, 2016
• Est. primary completion date: May 3, 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 20 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

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
• 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
• 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.

Locations

Country	Name	City	State
Mexico	Unidad de Farmacología Clínica de la Facultad de Medicina de la Universidad Nacional Autónoma de México	Nezahualcóyotl	Estado de México

Sponsors (3)

Lead Sponsor	Collaborator
Stendhal Americas, S.A.	LG Chem, Universidad Nacional Autonoma de Mexico

Country where clinical trial is conducted

Mexico, 

References & Publications (8)

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. Epub 2007 Oct 9. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Reyes-Hernández 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. Epub 2007 Oct 19. — View Citation

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. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of treatment-emergent adverse events	Incidence of adverse events occuring during the exposure to the study medications	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
Primary	Gemigliptin AUCt,ss Geometric Mean Ratio (and 90%CI)	AUCt,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	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
Secondary	Metformin AUCt,ss Geometric Mean Ratio (and 90%CI)	AUCt,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
Secondary	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
Secondary	Ctrough,ss	Lowest plasma concentration prior to the next dose administration at steady state	At steady state, on the sixth planned treatment day
Secondary	Aet,ss	cumulative amount of drug excreted in the urine during a dosing interval	At steady state, on the sixth planned treatment day
Secondary	CLss/F	Apparent drug clearance	At steady state, on the sixth planned treatment day
Secondary	CLR,ss	Renal drug clearance	At steady state, on the sixth planned treatment day
Secondary	MR	Metabolic ratio	At steady state, on the sixth planned treatment day
Secondary	Tmax	Time to maximum plasma concentration at steady state	At steady state, on the sixth planned treatment day