title: Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects.
abstract: Evogliptin is a newly developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which is expected to be combined with metformin for treating type 2 diabetes mellitus. We investigated the potential pharmacokinetic and pharmacodynamic interactions between evogliptin and metformin. A randomized, open-label, multiple-dose, six-sequence, three-period crossover study was conducted in 36 healthy male subjects. All subjects received three treatments, separated by 7-day washout intervals: evogliptin, 5 mg od for 7 days (EVO); metformin IR, 1,000 mg bid for 7 days (MET); and the combination of EVO and MET (EVO + MET). After the last dose in a period, serial blood samples were collected for 24 hours for pharmacokinetic assessments. During steady state, serial blood samples were collected for 2 hours after an oral glucose tolerance test, and DPP-4, active glucagon-like peptide-1, glucose, glucagon, insulin, and C-peptide were measured to assess pharmacodynamic properties. EVO + MET and EVO showed similar steady state maximum concentration and area under the concentration-time curve at steady state values for evogliptin; the geometric mean ratios (90% confidence interval) were 1.06 (1.01-1.12) and 1.02 (0.99-1.06), respectively. EVO + MET slightly reduced steady state maximum concentration and area under the concentration-time curve at steady state values for metformin compared to MET, with geometric mean ratios (90% confidence interval) of 0.84 (0.79-0.89) and 0.94 (0.89-0.98), respectively. EVO + MET and EVO had similar DPP-4 inhibition efficacy, but EVO + MET increased active glucagon-like peptide-1 and reduced glucose to larger extents than either EVO or MET alone. Our results suggested that EVO+MET could provide therapeutic benefits without clinically significant pharmacokinetic interactions. Thus, the EVO + MET combination is a promising option for treating type 2 diabetes mellitus.
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Su-Jin
authors: SJ
authors: Rhee
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: YoonJung
authors: Y
authors: Choi
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Clinical Trials Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors: SeungHwan
authors: S
authors: Lee
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Jaeseong
authors: J
authors: Oh
authors: Department of Clinical Development, Dong-A ST Co., Ltd., Seoul, Republic of Korea.
authors: Sung-Jin
authors: SJ
authors: Kim
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Seo Hyun
authors: SH
authors: Yoon
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Joo-Youn
authors: JY
authors: Cho
authors: Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: Kyung-Sang
authors: KS
authors: Yu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: C557982:4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010879:Piperazines; D008687:Metformin
keywords: DA-1229; DPP-4 inhibitor; OGTT; drug interaction; type 2 diabetes