Interaction potential of Carmegliptin with P-glycoprotein (Pgp) transporter in healthy volunteers

Figures & data

Table 1. In vitro P-glycoprotein transporter investigation.

		Cell lines used to study P-glycoprotein (transport ratios in apical direction)
		Control cells		Cells expressing human protein		Cells expressing mouse protein
Compound	Inhibitor	MDCKII	LLCPK	M-MDR1	LMDR1	Lmdr1a
Digoxin (tracer)	–	5.3	1.4	10.7	14.3	11.8
	Verapamil (100 µM)	1.3	–	2.3	1.1	1.2
Carmegliptin (4 µM)	–	3.5–4.8	1.4	9.7	5.5	4.2
	Verapamil (100 µM)	1.2	–	1.8	0.8	0.9
Digoxin	–	–	–	16.0/18.7*	–	–
	Carmegliptin (30 µM)	–	–	28.7/22.3*	–	–

*Results of two independent experiments.

Table 2. Summary of demographic characteristics of the healthy male volunteers (n = 16).

Parameter	Value
Race no. (%)
White	13 (81)
Black	3 (19)
Age, years
Mean (SD)	35.3 (11.1)
Range	18–48
Weight, kg
Mean (SD)	84.5 (8.8)
Range	64.1–97.7
Height, cm
Mean (SD)	180.4 (7.0)
Range	165–192
Body mass index, kg/m^2
Mean (SD)	26.0 (3.2)
Range	21.2–31.7

Figure 1. Carmegliptin: Mean plasma concentration vs time profiles on days 1, 10, and 15 (linear scale, 0–12 h).

Figure 2. Carmegliptin: Mean plasma concentration vs time profiles on days 1, 10, and 15 (log-linear scale, 0–48 h).

Figure 3. Carmegliptin: Mean cumulative urine recovery on days 1, 10, and 15.

Table 3. Carmegliptin: Summary of pharmacokinetic parameters on days 1, 10, and 15.

	Geometric mean (CV%)
	Carmegliptin single dose (day 1)	Carmegliptin + acute verapamil (day 10)	Carmegliptin + chronic verapamil (day 15)
n	16	16	16
AUC0–24 (h·ng/mL)	2410 (27.8)	2950 (25.5)	3620 (28.0)
AUClast (h·ng/mL)	3010 (26.4)	3650 (24.1)	4280 (26.7)
AUCinf (h·ng/mL)	3570 (23.9)	4250 (23.4)	4590 (26.3)
Cmax (ng/mL)	342 (42.2)	505 (48.9)	522 (42.3)
tmax (h)^a	3.00 (1.50–6.00)	0.75 (0.48–5.98)	1.50 (0.50–6.00)
t1/2 (h)	22.4 (18.9)	21.8 (18.8)	14.4 (12.4)
CL/F (L/h)	42.0 (23.9)	35.3 (23.4)	32.7 (26.3)
Vz/F (L)	1360 (30.0)	1110 (30.0)	678 (30.0)
Fe (%)	26.0 (22.7)	33.1 (17.7)	38.7 (18.1)
CLr (L/h)	12.9 (14.4)	13.6 (10.1)	13.6 (14.7)

^aMedian (range) for t_max.

Figure 4. Verapamil: Mean plasma concentration vs time profiles on days 7, 10, and 15 (linear scale, 0–24 h).

Table 4. Norverapamil: Summary of pharmacokinetic parameters on days 7 and 10.

	Geometric Mean (CV%)
	Verapamil single dose (day 7)	Carmegliptin + acute verapamil (day 10)
n	16	16
AUC0–6 (h ng/mL)	203 (36.6)	185 (34.1)
Cmax(6 h) (ng/mL)	63.8 (49.2)	51.2 (39.5)
tmax (h)^a	1.00 (0.50–4.00)	0.99 (0.48–4.00)

^aMedian (range) for t_max.

Table 5. Verapamil: Summary of pharmacokinetic parameters on days 7 and 10.

	Geometric mean (CV%)
	Verapamil single dose (day 7)	Carmegliptin + acute verapamil (day 10)
n	16	16
AUC0–6 (h·ng/mL)	198 (60.5)	177 (59.3)
Cmax(6 h) (ng/mL)	87.4 (92.3)	72.8 (83.7)
tmax (h)^a	0.75 (0.50–3.00)	0.75 (0.48–3.02)

^aMedian (range) for t_max.

Figure 5. Norverapamil: Mean plasma concentration vs time profiles on days 7, 10, and 15 (linear scale, 0–24 h).