Pharmacokinetic and Pharmacodynamic Comparison of Two Formulations of a Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg: A Randomized, Open-Label, Single-Dose, Two-Way Crossover Study

Figures & data

Table 1 In Vitro Accelerated Stability Test Results for Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg as Bilayer Tablet or Monolayer Tablet

Formulation	Storage Condition	Time	Recovery (%)		Impurities (%)
			Gemigliptin	Rosuvastatin	Total
Bilayer tablet	40 ± 2°C 75 ± 5% RH	3 months	98.43	99.20	1.92
		6 months	97.70	97.00	2.39
Monolayer tablet	40 ± 2°C 75 ± 5% RH	3 months	97.70	97.87	4.33
		6 months	97.63	95.03	7.55
Acceptance criteria			90–110	90–110	≤ 5.0

Note: Data are expressed as mean of 3 independent assays.

Abbreviation: RH, relative humidity.

Table 2 Pharmacokinetic Parameters of Gemigliptin, LC15-0636 and Rosuvastatin After a Single Administration of Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg as Bilayer Tablet or Monolayer Tablet

PK Parameter	Bilayer Tablet (N=45)	Monolayer Tablet (N=45)	Geometric Mean Ratio^a  (90% Confidence Interval)
Gemigliptin
Tmax (h)	1.50 [0.50–5.00]	1.50 [0.50–5.02]	–
Cmax (μg/L)	53.62 ± 16.31	55.74 ± 19.83	0.9798 (0.8998–1.0669)
AUClast (h*μg/L)	602.70 ± 105.47	624.34 ± 127.62	0.9714 (0.9491–0.9941)
AUCinf (h*μg/L)	636.83 ± 112.76	659.97 ± 135.15	0.9707 (0.9488–0.9931)
t1/2 (h)	18.43 ± 1.96	18.49 ± 2.31	–
CL/F (L/h)	81.04 ± 14.84	79.01 ± 16.66	–
Vd/F (L)	2148.23 ± 434.66	2106.61 ± 530.72	–
LC15-0636
Tmax (h)	4.00 [1.02–6.00]	3.00 [1.00–8.00]	–
Cmax (μg/L)	10.35 ± 3.92	10.02 ± 3.30	1.0269 (0.9593–1.0992)
AUClast (h*μg/L)	246.03 ± 34.74	246.31 ± 36.30	0.9998 (0.9844–1.0154)
AUCinf (h*μg/L)	289.09 ± 40.02	292.24 ± 41.91	0.9900 (0.9754–1.0050)
t1/2 (h)	26.86 ± 3.68	27.61 ± 4.73	–
Metabolic ratio^b	0.42 ± 0.08	0.41 ± 0.09	–
Rosuvastatin
Tmax (h)	4.00 [1.00–5.00]	4.00 [2.00–6.00]	–
Cmax (μg/L)	32.92 ± 15.25	32.97 ± 18.68	1.0233 (0.9370–1.1175)
AUClast (h*μg/L)	344.06 ± 139.01	347.92 ± 150.14	0.9931 (0.9471–1.0413)
AUCinf (h*μg/L)	351.58 ± 140.79	355.11 ± 151.37	0.9927 (0.9486–1.0389)
t1/2 (h)	13.44 ± 5.23	13.65 ± 4.22	–
CL/F (L/h)	67.90 ± 30.84	67.07 ± 29.22	–
Vd/F (L)	1281.39 ± 620.11	1337.01 ± 796.07	–

Notes: Data are expressed as mean ± standard deviation, except for T_max, which is expressed as median [minimum – maximum]. ^aGeometric mean ratio is the ratio of bilayer tablet to monolayer tablet. ^bRatio of AUC_last of LC15-0636 (metabolite) to AUC_last of gemigliptin (parent drug).

Abbreviations: AUC_inf, area under concentration–time curve (AUC) from 0 to infinity; AUC_last, AUC from 0 to last measurable time point; CL/F, apparent clearance; C_max, maximum plasma concentration; V_d/F, apparent volume of distribution; T_max, time to reach C_max; t_1/2, half-life.

Figure 1 Mean plasma concentration–time profiles of (A) gemigliptin, (B) LC15-0636 and (C) rosuvastatin after a single administration of fixed-dose combination of gemigliptin/rosuvastatin 50/20 mg as bilayer tablet or monolayer tablet.

Note: Error bars represent standard deviation.

Table 3 Plasma Dipeptidyl Peptidase-4 (DPP-4) Activity Inhibition from Baseline After a Single Administration of Fixed-Dose Combination of Gemigliptin/Rosuvastatin 50/20 mg as Bilayer Tablet or Monolayer Tablet

PD Parameter	Bilayer Tablet (N=45)	Monolayer Tablet (N=45)	Geometric Mean Ratio^a  (90% Confidence Interval)
DPP-4 activity inhibition (%)
AUEClast (h*%)	4279.94 ± 430.48	4295.02 ± 293.48	0.9915 (0.9807–1.0025)
Imax (%)	81.24 ± 3.68	81.43 ± 3.43	0.9970 (0.9871–1.0069)

Notes: Data are expressed as mean ± standard deviation. ^aGeometric mean ratio is the ratio of bilayer tablet to monolayer tablet.

Abbreviations: AUEC_last, area under plasma DPP-4 activity inhibition from baseline-time curve from 0 to last measurable time point; I_max, maximum inhibition of DPP-4 activity.

Figure 2 Mean plasma dipeptidyl peptidase-4 activity-time profiles after a single administration of fixed-dose combination of gemigliptin/rosuvastatin 50/20 mg as bilayer tablet or monolayer tablet.

Note: Error bars represent standard deviation.