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

Figures & data

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.

Table 1 Pharmacokinetic parameters for evogliptin and metformin, measured at steady state, after the last dose in a 7-day interval of EVO, MET, or EVO + MET treatment

Pharmacokinetic parameters (n=33)	Evogliptin		GMR (90% CI)	Metformin		GMR (90% CI)
	EVO + MET	EVO		EVO + MET	MET
Tmax,ss (h)	5.0 (1.0–7.0)	4.0 (1.0–7.0)		2.0 (0.5–4.1)	1.5 (0.5–3.0)
Cmax,ss (μg/L)	5.9±1.2	5.5±1.1	1.06 (1.01–1.12)	1,468.4±436.9	1,724.4±359.0	0.84 (0.79–0.89)
AUCτ,ss (μg⋅h/L)	91.4±17.1	89.6±18.0	1.02 (0.99–1.06)	9,121.2±2,415.6	9,616.0±1,974.8	0.94 (0.89–0.98)
CLss/F (L/h)	56.9±13.6	58.4±13.9		117.5±31.2	108.3±22.3
t1/2ss (h)	26.3±12.4	33.2±18.2		7.5±1.8	7.2±2.1
feτ,ss (%)	24.6±6.8	22.6±5.9		31.8±7.4	34.7±6.4
CLR,ss (L/h)	13.6±3.4	12.8±3.3		35.7±8.1	37.1±8.4

Notes: Data are presented as the arithmetic mean ± standard deviation, except for T_max,ss, which is presented as the median (min–max). GMR, geometric mean ratio of EVO + MET to EVO or EVO + MET to MET, as indicated.

Abbreviations: AUC_τ,SS, area under the concentration–time curve within a dosing interval (eg, 24 h for evogliptin and 12 h for metformin) at steady-state; bid, twice daily; C_max,ss, maximum concentration at steady state; CI, confidence interval; CL_R,ss, steady state renal clearance; CL_ss/F, apparent clearance at steady state; EVO, evogliptin, 5 mg od for 7 days; fe_τ,ss, fraction of dose excreted unaltered in urine within a dosing interval, at steady state; max, maximum; MET, metformin IR, 1,000 mg bid for 7 days; min, minimum; od, once daily; t_1/2ss, terminal half-life at steady state; T_max,ss, time to maximum concentration at steady state; EVO + MET, coadministration of EVO and MET.

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.

Table 2 Comparison of the inhibitory effect of evogliptin on DPP-4 activity, measured at steady state, after the last dose in a 7-day interval of EVO or EVO + MET treatment

Pharmacodynamic parameters (n=33)	EVO + MET	EVO	GMR (90% CI)
AUECτ,ss (%⋅h)	2,105.1±72.1	2,096.5±74.1	1.00 (0.99–1.02)
Emax,ss (%)	91.1±1.7	90.5±2.0	1.01 (1.00–1.02)
T80% (h)	24.0 (10.8–24.0)	24.0 (11.8–24.0)

Notes: Data are presented as the arithmetic mean ± standard deviation, except for T_80%, which is presented as the median (min–max). GMR, geometric mean ratio of EVO + MET to EVO.

Abbreviations: AUEC_τ,ss, area under the effect–time curve over the dosing interval (eg, 24 hours) at steady state; bid, twice daily; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; E_max,ss, maximum (inhibitory) effect on DPP-4 activity at steady state; EVO, evogliptin, 5 mg od for 7 days; h, hours; max, maximum; MET, metformin IR, 1,000 mg bid for 7 days; min, minimum; od, once daily; T_80%, time period that exhibited at least 80% inhibition of DPP-4 activity; EVO + MET, coadministration of EVO and MET.

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.

Table 3 Comparisons of the areas under the concentration–time curves for active GLP-1, glucose, glucagon, insulin, and C-peptide, measured during oral glucose tolerance test, delivered before (baseline) and after treatments with EVO, MET, and EVO + MET

Pharmacodynamic measurements (n=33)	Baseline	EVO	MET	EVO + MET	Post hoc comparison between treatments (P-value)
Active GLP-1 (pM⋅h)	17.9±25.4	29.8±26.7	22.2±11.1	44.9±25.3*	EVO > MET	0.548
					EVO < EVO + MET	0.041
					MET < EVO + MET	0.001
Glucose (mg⋅h/dL)	290.1±41.8	249.8±28.9*	247.3±26.6*	224.4±22.9*	EVO > MET	0.989
					EVO > EVO + MET	0.006
					MET > EVO + MET	0.016
Glucagon (pg⋅h/mL)	137.4±31.1	119.0±26.8	145.5±33.5	142.3±29.2	EVO < MET	0.003
					EVO < EVO + MET	0.012
					MET > EVO + MET	0.972
Insulin (μL U⋅h/mL)	119.4±63.9	84.6±37.3*	68.5±31.6*	66.8±25.9*	EVO > MET	0.411
					EVO > EVO + MET	0.322
					MET > EVO + MET	0.998
C-peptide (ng⋅h/mL)	16.4±5.0	13.7±3.8*	11.5±3.4*	11.9±3.1*	EVO > MET	0.100
					EVO > EVO + MET	0.210
					MET < EVO + MET	0.984

Notes: Data are presented as the arithmetic mean ± standard deviation or P-value. Significant differences compared to baseline are indicated with *P<0.05 based on ANOVAs with Tukey’s post hoc.

Abbreviations: ANOVA, analysis of variance; bid, twice daily; EVO, evogliptin, 5 mg od for 7 days; GLP-1, glucagon-like peptide-1; MET, metformin IR, 1,000 mg bid for 7 days; od, once daily; EVO + MET, coadministration of EVO and MET.

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.