Abstract
Purpose
The aim of this study was to assess the pharmacokinetic interactions between a newly
developed dipeptidyl peptidase (DPP)-4 inhibitor, gemigliptin, and metformin in healthy
Mexican male volunteers, and the differences in the pharmacokinetic profile of gemigliptin
between Korean and Mexican healthy volunteers.
Methods
This was a multiple-dose, randomized, open-label, 3-way, 3-period crossover study.
Subjects were randomized to 1 of 3 treatment sequences and received gemigliptin 50
mg once a day, metformin1000 mg BID, or both drugs during a 7-day treatment period,
and underwent sampling for pharmacokinetic analysis and tolerability assessments.
Point estimates and 90% CIs of Cmax,ss and AUCτ,ss least squares mean (LSM) ratios of the concurrent administration of gemigliptin + metformin
to the administration of monotherapy with either drug were obtained, and the pharmacokinetic
profile of gemigliptin observed was compared with that in healthy Korean volunteers
studied during the initial development of gemigliptin.
Findings
The coadministration of gemigliptin + metformin did not affect the pharmacokinetic
characteristics of gemigliptin (LSM ratio [90% CI] for Cmax,ss and AUCτ,ss: 0.98 [0.87–1.10] and 0.94 [0.91–0.98], respectively) or metformin (LSM ratio [90%
CI] for Cmax,ss and AUCτ,ss: 0.97 [0.88–1.08] and 1.02 [0.93–1.12], respectively) when administered as monotherapy
and was well tolerated. In contrast with Korean healthy volunteers, Mexican subjects
showed a modestly higher gemigliptin exposure (LSM ratio [90% CI] for AUCτ,ss: 1.22 [1.14–1.31]).
Implications
The results of this study support, in ethnically different populations, the absence
of drug–drug interactions between gemigliptin and metformin previously shown in Korean
healthy volunteers. Considering the flat effect–concentration curve and wide therapeutic
range of gemigliptin, the pharmacokinetic profile of gemigliptin observed in healthy
Mexican and Korean subjects suggests that gemigliptin use in Mexican patients may
be associated with outcomes, in terms of efficacy and tolerability, similar to those
observed in the Korean population. ClinicalTrials.gov identifier: NCT03310749.
Key words
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References
- Féderation Internationale de Diabète, Atlas of Diabetes of the FID. Belgium2015
- Life Expectancy Gains 1990-2012 and principal causes of death 2012 [online].(Available at:) (Accessed: 20 January, 2015)
- Dissonant health transition in the states of Mexico, 1990-2013: a systematic analysis for the Global Burden of Disease Study. 2013.Lancet. 2016; 388: 2386-2402
- Beta cell function and insulin resistance.Front Endocrinol (Lausanne). 2013; 4
- Diabetes. Advances in diagnosis and treatment.JAMA. 2015; 314: 1052-1062
- Trends in all cause and cardiovascular disease mortality among women and men with and without diabetes mellitus in the Framingham Heart Study, 1950 to 2005.Circulation. 2009; 119: 1728-1735
- Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias and reverse causation.Diabetes Care. 2015; 38: 264-270
- Mortality and cardiovascular disease in type 1 and type 2 diabetes.N Engl J Med. 2017; 376: 1407-1418
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).The Lancet. 1998; 352: 837-853
- Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomized control trials.Lancet Diabetes Endocrinol. 2017; 5: 431-437
- Management of hyperglycemia in type 2 diabetes: A patient centered approach.Diabetes Care. 2012; 35: 1364-1379
- Medication adherence in type 2 diabetes: The ENTRED study 2007, a French population-based study.PLoS One. 2012; 7: e32412
- Factors associated with nonadherence to diet and physical activity among Nepalese type 2 diabetes patients; a cross sectional study.BMC Res Notes. 2014; 7 (https://bmcresnotes.biomedcentral.com/): 758
- Adherence to therapies in patients with type 2 diabetes.Diabetes Ther. 2013; 4: 175-194
- Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo.Eur J Pharmacol. 2016; 788: 54-64
- Pharmacokinetics, pharmacodynamics and tolerability of the dipeptidyl peptidase-4 inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized double blind, placebo controlled, ascending dose, phase I study.Clin Ther. 2008; 30: 1817-1839
- Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers.Br J Clin Pharmacol. 2009; 68: 833-890
- Absorption, metabolism and excretion of [14]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor in humans.Xenobiotica. 2014; 44: 522-530
- Pharmacokinetic and pharmacodynamics interaction between gemigliptin and metformin in healthy subjects.Clin Drug invest. 2014; 34: 383-393
- A multicenter, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes.Diabetes Obes Metab. 2013; 15: 410-416
- Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone.Diabetes Obes Metab. 2013; 15: 523-530
- Tutorial in biostatistics.Sample sizes for clinical trials with normal data. Stat. Med. 2004; 23: 1921-1986
- Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.Biopharm. Drug Dispos. 2007; 28: 307-313
- Publication number NOM-177-SSA1-2013 [Secretaría de Salud website].(Available at:) (Accessed: 3 August 2018)
- Bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors: a report of five cases.J Diabetes Investig. 2017; 8: 48
- Effect of race and ethnicity on vildagliptin efficacy: a pooled analysis of phase II and III studies.Diabetes Obes Metab. 2017; 19: 429-435
- Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis.Diabetologia. 2013; 56: 696-708
- Beta-cell function is a major contributor to oral glucose tolerance in high risk relatives of four ethnic groups in the US.Diabetes. 2002; 51: 2170-2178
- Changes in serum true insulin and C-peptide levels during oral glucose tolerance tests in Koreans with glucose intolerance.J Korean Diabetes Assoc. 1998; 22: 192-198
- Predicting efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: association of glycated hemoglobin reduction with serum eicosapentaenoic acid and docosahexaenoic acid levels.J Diabetes Investig. 2012; 3: 464-467
- Incretin-based drugs for type 2 diabetes: focus on East Asian perspectives.J Diabetes Investig. 2016; 7: 102-109
- Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities and impact of genetic variation.Pharmacol Ther. 2013; 138: 103-141
- A comparative study of CYP3A4 polymorphisms in Mexican Amerindians and mestizo populations.Pharmacology. 2008; 81: 97-103
- Gemigliptin: An update of its clinical use in the management of type 2 diabetes mellitus.Diabetes Metab J. 2016; 40: 339-353
- A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes.Diabetes Obes Metab. 2010; 12: 1113-1119
Article info
Publication history
Published online: September 22, 2018
Accepted:
August 22,
2018
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
