Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD

Figures & data

Table 1 Baseline demographics and clinical characteristics (PK sub-study)

Patient characteristics	GFF MDI 14.4/10 μg N=91	GP MDI 14.4 μg N=79	FF MDI 10 μg N=80	Placebo MDI N=42	All patients N=292
Mean age, years (SD)	60.4 (7.9)	61.6 (8.7)	60.5 (8.8)	59.9 (9.0)	60.7 (8.5)
Male, n (%)	54 (59.3)	45 (57.0)	43 (53.8)	26 (61.9)	168 (57.5)
Mean BMI, kg/m^2 (SD)	28.8 (5.9)	29.8 (6.4)	28.5 (6.6)	28.3 (5.2)	28.9 (6.1)
Caucasian, n (%)	87 (95.6)	69 (87.3)	75 (93.8)	40 (95.2)	271 (92.8)
Current smoker,a n (%)	57 (62.6)	50 (63.3)	48 (60.0)	28 (66.7)	183 (62.7)
Mean pack-yearsb (SD)	55.3 (34.1)	53.8 (29.6)	53.8 (28.8)	58.3 (35.7)	54.9 (31.7)
ICS at baseline, n (%)	30 (33.0)	26 (32.9)	22 (27.5)	14 (33.3)	92 (31.5)
Mean CAT scorec,d (SD)	19.9 (6.9)	20.3 (7.7)	19.5 (7.4)	20.0 (6.5)	19.9 (7.2)
Mean mMRC gradee (SD)	1.8 (1.0)	2.0 (1.1)	2.1 (1.0)	2.0 (1.1)	2.0 (1.0)

Notes:

a Former smoker was defined as those who have stopped smoking for at least 6 wks prior to first screening visit.

b Number of pack-years smoked = (number of cigarettes per day/20) × number of years smoked.

c n=91, n=78, n=79, n=42, n=290.

d The total score is the sum of eight CAT item scores and range from 0–40.

e Grades range between 0–4, where 4 represents the highest level of breathlessness.

Abbreviations: PK, pharmacokinetic; GFF, glycopyrronium/formoterol fumarate dihydrate; MDI, metered dose inhaler; GP, glycopyrronium; FF, formoterol fumarate dihydrate; BMI, body mass index; ICS, inhaled corticosteroid; CAT, COPD Assessment Test; mMRC, modified Medical Research Council dyspnea scale.

Table 2 PK parameters of glycopyrronium and formoterol on Day 1 and Week 12 (PK population)

PK parameters	Day 1 (after single dose)				Week 12 (after chronic dosing)
	Glycopyrronium		Formoterol		Glycopyrronium		Formoterol
	GFF MDI 14.4/10 μg N=83	GP MDI 14.4 μg N=68	GFF MDI 14.4/10 μg N=83	FF MDI 10 μg N=70	GFF MDI 14.4/10 μg N=83	GP MDI 14.4 μg N=68	GFF MDI 14.4/10 μg N=83	FF MDI 10 μg N=70
AUC0–12 geometric mean, h⋅pg/mL (CV%)	(n=48) 37.20 (52.4)	(n=36) 40.19 (63.7)	(n=60) 45.91 (37.4)	(n=48) 41.89 (35.4)	(n=48) 78.67 (64.9)	(n=39) 77.85 (60.1)	(n=49) 70.71 (46.4)	(n=40) 66.65 (52.7)
Cmax geometric mean, pg/mL (CV%)	(n=73) 15.59 (82.8)	(n=58) 15.19 (83.8)	(n=74) 8.82 (49.4)	(n=62) 7.52 (47.9)	(n=60) 22.45 (86.9)	(n=52) 18.67 (79.3)	(n=60) 11.92 (49.3)	(n=52) 10.98 (51.8)
tmax median, h (min, max)	(n=73) 0.08 (0.03, 7.98)	(n=58) 0.08 (0.03, 1.05)	(n=74) 0.41 (0.03, 4.03)	(n=62) 1.00 (0.03, 12.00)	(n=60) 0.08 (0.03, 4.45)	(n=52) 0.08 (0.03, 12.00)	(n=60) 0.37 (0.03, 8.00)	(n=51) 0.97 (0.08, 7.97)

Abbreviations: PK, pharmacokinetic; GP, glycopyrronium; GFF, glycopyrronium/formoterol fumarate dihydrate; MDI, metered dose inhaler; FF, formoterol fumarate dihydrate; CV, coefficient of variation.

Figure 1 Plasma concentrations after single and chronic dosing.

Notes: (A) Glycopyrronium from GFF MDI and GP MDI; (B) formoterol from GFF MDI and FF MDI (PK population).
Abbreviations: GFF, glycopyrronium/formoterol fumarate dihydrate; MDI, metered dose inhaler; GP, glycopyrronium; FF, formoterol fumarate dihydrate; PK, pharmacokinetic.

Table 3 Accumulation ratios (Week 12/Day 1) for glycopyrronium and formoterol following GFF MDI and GP MDI or FF MDI administration (PK population)

PK parameters	Glycopyrronium
	GFF MDI 14.4/10 μg				GP MDI 14.4 μg
	n Week 12/Day 1	Accumulation ratio of geometric LSMa	90% CI	Intra-subject CV%	n Week 12/Day 1	Accumulation ratio of geometric LSMa	90% CI	Intra-subject CV%
AUC0–12	48/48	2.30	2.04, 2.59	30.1	39/36	1.99	1.65, 2.42	48.3
Cmax	60/73	1.40	1.22, 1.59	43.5	52/58	1.26	1.06, 1.50	54.9
	Formoterol
	GFF MDI 14.4/10 μg				FF MDI 10 μg
	n Week 12/Day 1	Accumulation ratio of geometric LSMa	90% CI	Intra-subject CV%	n Week 12/Day 1	Accumulation ratio of geometric LSMa	90% CI	Intra-subject CV%
AUC0–12	49/60	1.52	1.36, 1.69	30.3	40/48	1.62	1.41, 1.86	36.7
Cmax	60/74	1.32	1.21, 1.43	26.4	52/62	1.51	1.34, 1.71	38.1

Notes:

a Ratio of exponentiated mean difference of log-transformed PK parameter for Week 12 versus Day 1. A separate model was fit for each treatment. The CI is from a mixed model with visit as a fixed effect and patient as a random effect.

Abbreviations: GP, glycopyrronium; GFF, glycopyrronium/formoterol fumarate dihydrate; MDI, metered dose inhaler; FF, formoterol fumarate dihydrate; PK, pharmaco- kinetic; LSM, least squares mean; CV, coefficient of variation.

Figure 2 Relative bioavailability for glycopyrronium and formoterol following GFF MDI and GP MDI or FF MDI administration (GFF MDI/monocomponent MDI) (PK population).

Note: Vertical bars are 90% CI of the ratio (GFF MDI/monocomponent MDI) of geometric LSM.
Abbreviations: GFF, glycopyrronium/formoterol fumarate dihydrate; MDI, metered dose inhaler; GP, glycopyrronium; FF, formoterol fumarate dihydrate; PK, pharmacokinetic; LSM, least squares mean.