The Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide 400 μg Administered by Inhalation as Single and Multiple (Twice Daily) Doses in Healthy Chinese Participants

Figures & data

Figure 1 Study Design.

Table 1 Participant Demographics and Characteristics (N = 20)

Parameter	Aclidinium Bromide 400 μg
Age, years (mean [SD])	27.2 (5.2)
Male, n (%)	11 (55.0)
BMI, kg/m^2 (mean [SD])	23.0 (2.3)
Normal weight (≥18.5 and <25 kg/m^2), n (%)	14 (70.0)
Pre-obese (≥25 and <30 kg/m^2), n (%)	6 (30.0)

Abbreviations: BMI, body mass index; SD, standard deviation.

Figure 2 Geometric Mean Plasma Concentration (pg/mL) of (A) Aclidinium, (B) LAS34823 and (C) LAS34850 Versus Time: Day 1 and Day 9.

Notes: Data points are displayed only if ≥3 concentrations are available for each timepoint. Data are plotted on a semi-logarithmic scale on Supplementary Figure 1.

Abbreviation: h, hours.

Table 2 Pharmacokinetic Parameters of Aclidinium Bromide and Its Metabolites LAS34823 and LAS34850, Following a Single Dose (Day 1) and Following Multiple Dosing (Day 9 After 5 Days of Repeated BID Dosing) of Aclidinium Bromide 400 μg (N = 20)

Parameter		Aclidinium Bromide PK Parameters		LAS34823 PK Parameters		LAS34850 PK Parameters
		Single Dose (Day 1)	Multiple Dose (Day 9)	Single Dose (Day 1)	Multiple Dose (Day 9)	Single Dose (Day 1)	Multiple Dose (Day 9)
Cmax, pg/mL	Gmean (gCV%)	238.6 (51.7)	341.3 (40.2)	164.0 (45.1)	294.1 (39.9)	3831 (25.0)	4891 (16.5)
	Min, max	86.9, 544.0	136.0, 645.0	76.6, 368.0	152.0, 650.0	2530.0, 5490.0	3150.0, 6110.0
tmax, h	Median	0.08	0.08	0.08	0.08	3.00	2.50
	Min, max	0.08, 0.10	0.08, 0.10	0.08, 0.50	0.08, 0.50	2.00, 3.00	1.50, 3.00
AUCinf (h·pg/mL)	Gmean (gCV%)	266.1 (59.2)	—	684.4 (48.0)	—	29,970.0 (17.6)	—
	Min, max	64.0, 556.0	—	305.0, 1590.0	—	21,000.0, 40,400.0	—
AUCτ (h·pg/mL)	Gmean (gCV%)	167.1 (40.2)	357.8 (32.3)	438.1 (37.3)	1031.0 (25.6)	22,730.0 (18.6)	33,910.0 (15.3)
	Min, max	60.7, 276.0	217.0, 720.0	228.0, 799.0	640.0, 1600.0	15,600.0, 29,000.0	23,600.0, 45,400.0
AUClast (h·pg/mL)	Gmean (gCV%)	208.9 (57.2)	609.4 (36.5)	550.4 (54.1)	1849.0 (25.5)	29,010.0 (18.0)	50,370.0 (16.8)
	Min, max	52.2, 414.0	270.0, 1290.0	228.0, 1310.0	1270.0, 3090.0	20,500.0, 38,500.0	34,600.0, 73,100.0
t1/2λz (h)	Gmean (gCV%)	13.5 (91.6)	21.4 (25.6)	10.0 (43.0)	17.7 (12.4)	8.3 (26.8)	12.7 (19.0)
	Min, max	3.1, 43.4	10.6, 35.7	5.1, 22.6	14.6, 22.2	5.0, 12.3	10.1, 21.5
CL/F (L/h)	Gmean (gCV%)	1503.0 (59.2)	1118.0 (32.3)	—	—	—	—
	Min, max	720.0, 6250.0	555.0, 1850.0	—	—	—	—
Vz/F (L)	Gmean (gCV%)	29,280.0 (45.5)	34,550.0 (40.9)	—	—	—	—
	Min, max	14,900.0, 62,100.0	14,800.0, 66,700.0	—	—	—	—
MRTinf (h)	Gmean (gCV%)	13.5 (95.2)	—	—	—	—	—
	Min, max	3.2, 42.7	—	—	—	—	—
Cmin (pg/mL)	Gmean (gCV%)	3.3 (56.3)	11.6 (41.2)	14.8 (31.5)	43.0 (28.6)	647.8 (20.8)	1223.0 (19.3)
	Min, max	0.6, 6.6	5.8, 27.5	8.4, 21.7	28.0, 74.4	454.0, 954.0	882.0, 1900.0
MRCmax	Gmean (gCV%)	—	—	0.69 (29.14)	0.86 (20.29)	16.05 (48.71)	14.33 (43.98)
	Min, max	—	—	0.37, 1.12	0.62, 1.50	7.71, 45.50	8.31, 37.70
MRAUCτ	Gmean (gCV%)	—	—	2.6 (26.6)	2.9 (23.0)	136.0 (39.6)	94.8 (32.6)
	Min, max	—	—	1.6, 4.2	2.1, 4.6	78.8, 362.0	54.1, 168.0
Cavg (pg/mL)	Gmean (gCV%)	—	29.8 (32.3)	—	86.0 (25.6)	—	2826.0 (15.3)
	Min, max	—	18.1, 60.0	—	53.3, 134.0	—	1970.0, 3780.0
TCP	Gmean (gCV%)	—	1.34 (52.38)	—	1.51 (46.61)	—	1.13 (16.83)
	Min, max	—	0.60, 4.11	—	0.64, 3.15	—	0.87, 1.59
Rac(Cmax)	Gmean (gCV%)	—	1.43 (44.18)	—	1.79 (45.61)	—	1.28 (20.40)
	Min, max	—	0.69, 3.24	—	0.71, 4.16	—	0.91, 1.76
Rac(Cmin)	Gmean (gCV%)	—	3.55 (50.32)	—	2.90 (37.70)	—	1.89 (22.90)
	Min, max	—	2.05, 14.20	—	1.81, 5.24	—	1.16, 2.63
Rac(AUC)	Gmean (gCV%)	—	2.14 (37.64)	—	2.35 (40.94)	—	1.49 (16.84)
	Min, max	—	1.13, 4.34	—	1.23, 4.77	—	1.18, 2.15
%Fluc	Gmean (gCV%)	—	1102.0 (34.7)	—	289.2 (35.3)	—	128.9 (14.9)
	Min, max	—	579.0, 2370.0	—	171.0, 713.0	—	101.0, 166.0

Notes: Data are expressed as geometric means, calculated using log transformed data.

Abbreviations: AUC_inf, area under the plasma concentration–time curve from zero to infinity; AUC_last, area under the plasma concentration–time curve from zero to the last quantifiable concentration; AUC_τ, area under the concentration–time curve during a dosage interval; BID, twice daily; C_avg, average drug concentration over a dosing interval; CI, confidence interval; CL/F, apparent total body clearance from plasma after extravascular administration; C_min, minimum observed drug concentration; C_max, maximum concentration; gCV, geometric coefficient of variation; Gmean, geometric mean; h, hours; MRAUC_τ, metabolite to parent ratio based on AUC_τ; MRC_max, metabolite to parent ratio based on C_max; MRT_inf, mean residence time of the unchanged drug in the systemic circulation; Rac_(AUC), accumulation ratio for AUC_τ; Rac_(Cmax), accumulation ratio for C_max; Rac_(Cmin), accumulation ratio for C_min; t_1/2λz, half-life associated with terminal slope of a semi-logarithmic concentration–time curve; TCP, temporal change parameter based on AUC; t_max, time to reach C_max; Vz/F, volume of distribution (apparent) following extravascular administration based on terminal phase; %Fluc, fluctuation index during a dosing interval.