Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects

Su-Jin Rhee, YoonJung Choi, SeungHwan Lee, Jaeseong Oh, Sung-Jin Kim, Seo Hyun Yoon, Joo-Youn Cho, Kyung-Sang Yu, Su-Jin Rhee, YoonJung Choi, SeungHwan Lee, Jaeseong Oh, Sung-Jin Kim, Seo Hyun Yoon, Joo-Youn Cho, Kyung-Sang Yu

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.

Keywords: DA-1229; DPP-4 inhibitor; OGTT; drug interaction; type 2 diabetes.

Figures

Figure 1
Figure 1
Study design. Notes: Subjects were randomly assigned to one of the indicated crossover treatment sequences (sequence A–F) on day 0, before the predose OGTT was administered. Abbreviations: bid, twice daily; EVO, evogliptin, 5 mg od for 7 days; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; OGTT, oral glucose tolerance test; PD, pharmacodynamics; PK, pharmacokinetic; EVO + MET, coadministration of EVO and MET.
Figure 2
Figure 2
Mean plasma concentration–time profiles of (A) evogliptin and (B) metformin after treatment with EVO, MET, or EVO + MET. Notes: Triangles represent values for EVO; squares represent values for MET; and open circles represent values for EVO + MET. Error bars represent standard deviations (n=33). Abbreviations: bid, twice daily; EVO, evogliptin, 5 mg od for 7 days; h, hours; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; EVO + MET, coadministration of EVO and MET.
Figure 2
Figure 2
Mean plasma concentration–time profiles of (A) evogliptin and (B) metformin after treatment with EVO, MET, or EVO + MET. Notes: Triangles represent values for EVO; squares represent values for MET; and open circles represent values for EVO + MET. Error bars represent standard deviations (n=33). Abbreviations: bid, twice daily; EVO, evogliptin, 5 mg od for 7 days; h, hours; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; EVO + MET, coadministration of EVO and MET.
Figure 3
Figure 3
Time course of the inhibition (%) of DPP-4 activity compared to baseline, after treatment with EVO or EVO + MET. Notes: Triangles represent EVO; open circles represent EVO + MET. The error bars represent the standard deviations (n=33). Abbreviations: bid, twice daily; DPP-4, dipeptidyl peptidase-4; EVO, evogliptin, 5 mg od for 7 days; h, hours; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; EVO + MET, coadministration of EVO and MET.
Figure 4
Figure 4
Mean concentration–time profiles during an oral glucose tolerance test for (A) active GLP-1, (B) glucose, (C) glucagon, (D) insulin, and (E) C-peptide, measured before (baseline) and after treatments with EVO, MET, and EVO + MET. Notes: Dotted lines, baseline; triangles, EVO; squares, MET; open circles, EVO + MET. Error bars represent the standard error of the mean (n=33). Abbreviations: bid, twice daily; EVO, evogliptin, 5 mg od for 7 days; GLP-1, glucagon-like peptide-1; h, hours; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; EVO + MET, coadministration of EVO and MET.

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