Effect of High-Fat Meal on the Pharmacokinetics and Safety of Valsartan/Amlodipine Fixed Dose Combination Tablets in Healthy Subjects

Figures & data

Figure 1 Subjects flow chart. Flow chart of the subjects in the fasted state (A). Flow chart of the subjects in the fed state (B). N: the number of subjects.

Table 1 The Ingredient List of High-Fat Meal

Nutrients	Total	Protein (Kcal)	Fat (Kcal)	Carbohydrate (Kcal)	Calories (Kcal)
Yili milk	250mL	32	85.5	50	167.5
Baked sausage	60g	43.4	76.7	21.4	141.5
Eggs	110g	45.5	88.8	7.9	142.2
Croissant	115g	34	283.6	209.8	527.4
Calories (Kcal)		154.9	534.6	289.1	978.6
Percentage of Calories (%)		15.8	54.6	29.5	100%

Notes: 1 g protein was calculated by 4 kcal calories, 1 g carbohydrate by 4 kcal calories, and lg fat by 9 kcal calories. The eggs were calculated by raw food weight.

Table 2 Demographic Information and Baseline Information of Subjects in Groups

Variables	Statistics	Fasted Group	Fed Group	Total
Total number		44	44	88
Sex (%)
Male		28 (63.6%)	29 (65.9%)	57 (64.8%)
Female		16 (36.4%)	15 (34.1%)	31 (35.2%)
Age, years	Mean (SD)	32.98±7.84	32.70±8.42	32.84±8.09
Height, cm	Mean (SD)	165.78±7.91	167.28±8.40	166.53±8.15
Weight, kg	Mean (SD)	62.89±7.47	63.60±8.54	63.25±7.98
BMI, kg/m^2	Mean (SD)	22.85±1.90	22.66±1.89	22.76±1.90

Notes: Data are the mean±SD, except sex (male/female), which is in %, BMI, body mass index, SD, standard deviation.

Figure 2 Arithmetic mean (SE) plasma concentration versus time profiles of valsartan (A), amlodipine (B) after single oral dose administration of valsartan/amlodipine tablet (80/5mg) under fed and fasted conditions.

Table 3 Mean Pharmacokinetic Parameter Values for Valsartan and Amlodipine

PK Parameter	Arithmetic Mean (SD)		Geometric Mean (CV (%))		Fed:Fasted Ratio
	Fasted^a	Fed^b	Fasted^a	Fed^b	GLS Mean Ratio (90% CI) ^c
valsartan
Cmax (ng/mL)	2888.34 (1426.15)	1411.14 (536.64)	2573.13 (49.38)	1323.76 (38.03)	51.45 (44.18–55.90)
AUC0–t (ng×h/mL)	16,115.53 (6503.42)	8937.32 (3356.51)	14,857.04 (40.35)	8351.09 (37.56)	56.21 (44.87–64.65)
AUC0–∞ (ng×h/mL)	16,547.62 (6663.39)	9296.81 (3430.08)	15,265.88 (40.27)	8717.52 (36.90)	57.10 (49.76–65.52)
AUMC0–t (h×h×ng/mL)	104,095.98 (44,552.74)	70,079.92 (36,113.49)	95,368.23 (42.80)	62,653.95 (51.53)	65.70 (55.95–77.14)
AUMC0–∞ (h×h×ng/mL)	118,908.41 (50,486.99)	83,587.42 (42,138.97)	108,963.96 (42.46)	75,157.41 (50.41)	68.97 (58.95–80.71)
t1/2(h)	5.46 (1.40)	5.83 (2.47)	5.31 (25.61)	5.46 (42.38)	102.83 (92.70–114.11)
Tmax (h)^d	3(1,7)	4.25 (2,5.5)	---	---	---
V/F (mL)	44,452.13 (20,825.24)	82,351.00 (51,729.98)	40,826.76 (46.85)	72,293.41 (62.82)	---
CL/F (mL/h)	5748.59 (2423.80)	9774.90 (3508.89)	5292.51 (42.16)	9176.92 (35.90)	---
MRT(h)	6.49 (1.05)	7.65 (1.54)	6.42 (16.23)	7.50 (20.18)	---
amlodipine
Cmax (ng/mL)	3.86 (0.83)	3.72 (0.92)	3.77 (21.55)	3.61 (24.65)	95.76 (88.33–104.24)
AUC0–t(ng×h/mL)	119.95 (27.67)	122.40 (28.92)	116.19 (23.07)	119.36 (23.63)	102.73 (93.99–112.28)
AUC0–∞(ng×h/mL)	174.78 (53.43)	184.89 (54.87)	166.34 (30.57)	177.84 (29.68)	106.91 (95.70–119.44)
AUMC0–t (h×h×ng/mL)	3443.87 (898.15)	3662.93 (952.11)	3300.73 (26.08)	3553.26 (25.99)
AUMC0–∞ (h×h×ng/mL)	11,030.36 (6557.73)	12,738.92 (6653.8) 2)	9688.67 (59.45)	11,422.31 (52.23)
t1/2(h)	40.81 (10.24)	45.02 (11.83)	39.74 (25.08)	43.70 (26.27)	109.96 (101.12–119.54)
Tmax (h)^d	5 (4.5–9)	5 (3–24)	---	---	---
V/F (mL)	1,799,681.41 (555,747.93)	1,819,424.12 (411,380.42)	1,739,618.25 (30.88)	1,772,425.44 (22.61)	---
CL/F (mL/h)	32,564.22 (17,163.63)	29,138.51 (7637.61)	30,344.29 (52.71)	28,115.10 (26.21)	---
MRT(h)	28.47 (1.88)	29.83 (1.87)	28.41 (6.60)	29.77 (6.28)	---

Notes: ^aFasted = valsartan/amlodipine tablet (80/5mg) administered in fasting state. ^bFed = valsartan/amlodipine tablet (80/5mg) administered after high-fat meal. ^cMeans, ratios, and CI are based on geometric means because data are analyzed on log scale. ^dValues are medians (minimum–maximum).

Abbreviations: AUC_0–t, area under the concentration–time curve from zero to the final measurable concentration; AUC_0–∞ =area under the concentration–time curve from time zero to infinity; Cmax, maximum concentration; t_1/2, elimination half-life; Tmax, Time to reach maximum concentration; V/F, Volume; MRT, mean residence time;CL/F, renal clearance.SD, standard deviation; CV =coefficient of variation; CI, confidence interval.