Safety, tolerability, and pharmacokinetics of single and repeat ascending doses of CHF6001, a novel inhaled phosphodiesterase-4 inhibitor: two randomized trials in healthy volunteers

Figures & data

Table 1 Demographic characteristics (safety population)

	Study 1 (SDDPI)							Study 2 (MDDPI)
	Part 1	Part 2						Part 1	Part 2
	Overall (N=20)	Placebo (N=13)	CHF6001					Overall (N=12)	Placebo (N=9)	CHF6001
			100 µg OD (N=8)	300 µg OD (N=8)	600 µg OD (N=9)	1,200 µg OD (N=9)	1,600 µg OD (N=7)			1,200 µg BID (N=9)	2,000 µg BID (N=9)	2,400 µg BID (N=9)
Age, years	35.5 (9.8)	33.2 (10.8)	42.5 (10.2)	29.5 (10.3)	29.8 (7.4)	32.4 (11.8)	33.4 (9.6)	36.4 (13.3)	31.1 (11.0)	41.4 (12.6)	31.1 (10.2)	35.8 (7.3)
Height, cm	180.1 (9.2)	175.5 (7.6)	174.0 (7.8)	178.6 (3.5)	179.9 (9.7)	179.7 (9.2)	177.9 (6.8)	174.4 (10.9)	175.9 (8.2)	171.1 (7.4)	177.7 (10.2)	177.3 (7.9)
BMI, kg/m^2	26.1 (3.0)	25.6 (2.6)	26.6 (2.3)	25.1 (3.2)	24.4 (3.3)	25.1 (3.9)	25.8 (2.5)	25.6 (4.3)	23.5 (2.4)	27.3 (2.7)	24.7 (4.0)	27.2 (2.7)
Race, n (%)
Caucasian	20 (100)	13 (100)	8 (100)	8 (100)	9 (100)	9 (100)	7 (100)	12 (100)	8 (88.9)	9 (100)	9 (100)	9 (100)
Othera	–	–	–	–	–	–	–	–	1 (11.1)	–	–	–
Sex, n (%)
Male	20 (100)	13 (100)	8 (100)	8 (100)	9 (100)	9 (100)	7 (100)	7 (58.3)	7 (77.8)	6 (66.7)	7 (77.8)	9 (100)
Female	–	–	–	–	–	–	–	5 (41.7)	2 (22.2)	3 (33.3)	2 (22.2)	–

Notes: Data are mean (SD) unless specified otherwise.

a Mixed race (black and Caucasian). Safety population is defined as all randomized subjects who had received at least one dose of study medication.

Abbreviations: BID, twice daily; BMI, body mass index; MDDPI, study medication administered via multi-dose dry-powder inhaler; OD, once daily; SDDPI, study medication administered via single-dose dry-powder inhaler.

Table 2 CHF6001 derived pharmacokinetic parameters following single doses (PK population)

CHF6001 dose	Pharmacokinetic parameter
	Cmax, pg/mL	tmax, h	AUC0–t, pg.h/mL	t½, h
SDDPI
20 µg (N=8)	18.9 (22.2)	0.08 (0.08, 2)	31.6 (91.3)	5.6 (9.3)a
100 µg (N=8)	63.8 (32.8)	1.74 (1.0, 2)	1,477 (33.8)	28.2 (0.0)b
200 µg (N=8)	140.2 (28.0)	1.03 (0.5, 2)	2,782 (18.9)	30.1 (29.7)c
400 µg (N=7)	194.7 (25.4)	2.0 (2, 6)	5,384 (24.9)	45.3 (40.8)a
800 µg (N=7)	432.4 (24.3)	2.0 (1.0, 4)	10,600 (28.7)	26.3 (1.0)a
1,600 µg (N=7)	730.0 (29.5)	2.0 (0.5, 2)	17,990 (32.6)	27.4 (NC)d
2,000 µg (N=5)	982.6 (11.6)	2.0 (1.5, 2)	25,550 (25.3)	37.3 (15.5)a
MDDPI
2,400 µg (N=9)	1,234 (19.6)	3.0 (2, 4)	35,178 (23.4)	49.1 (40.1)e
4,000 µg (N=8)	2,551 (19.2)f	3.0 (2, 4)f	75,754 (24.9)f	44.0 (17.7)e
4,800 µg (N=8)	2,723 (22.3)	3.0 (1.5, 6)	77,409 (25.6)	40.0 (35.6)f

Notes: Data are geometric mean (% coefficient of variation), except t_max which is median (range). PK population is defined as all subjects in the safety population who had at least one valid PK measurement and who had no major PK-related protocol deviations.

a n=3;

b n=2;

c n=5;

d n=1;

e n=4;

f n=7.

Abbreviations: AUC_0–t, area under the curve from administration to last measurable concentration; C_max, maximum plasma concentration; PK, pharmacokinetics; MDDPI, study medication administered via multi-dose dry-powder inhaler; NC, not calculated (geometric mean from only one subject); SDDPI, study medication administered via single-dose dry-powder inhaler; t_½, terminal elimination half life; t_max, time to maximum concentration.

Figure 1 CHF6001 plasma pharmacokinetic–time profile following single doses (PK population).

Notes: Data are mean. PK population is defined as all subjects in the safety population who had at least one valid PK measurement and who had no major PK-related protocol deviations.
Abbreviations: PK, pharmacokinetics; MDDPI, study medication administered via multi-dose dry-powder inhaler; SDDPI, study medication administered via single-dose dry-powder inhaler.

Table 3 CHF6001 derived pharmacokinetic parameters following OD or BID administration (PK population)

CHF6001 dose	Day	Pharmacokinetic parameter
		Cmax, pg/mL	tmax, h	AUC0–24 h or AUC0–12 h*, pg.h/mL	Weighted AUC**, pg.h/mL.µg	CL/F, mL/min	Racc
SDDPI
100 µg OD (N=7)	1	65.4 (28.9)	1.5 (0.08, 2.0)	796.3 (37.7)
	7	165.3 (33.8)	1.0 (0.5, 2)	2,304 (41.1)	23.0 (41.1)	723 (41.1)	2.89 (16.6)
300 µg OD (N=8)	1	178.6 (22.4)	2.0 (1.0, 4)	2,340 (24.5)
	7	410.0 (40.3)	1.0 (1.0, 4)	5,815 (44.7)	19.4 (44.7)	860 (44.7)	2.49 (31.8)
600 µg OD (N=9)	1	290.0 (22.3)	1.5 (1.0, 6)	4,240 (21.7)
	7	701.7 (24.7)	2.0 (1.0, 4)	10,460 (28.2)	17.4 (28.2)	956 (28.2)	2.47 (20.2)
1,200 µg OD (N=9)	1	628.3 (28.0)	2.1 (2, 8)	9,465 (26.4)
	7	1,689.9 (28.0)	2.0 (1.5, 2)	25,920 (26.6)	21.6 (26.6)	772 (26.6)	2.74 (28.2)
1,600 µg OD (N=6)	1	710.4 (41.5)	2.0 (1.0, 2)	10,640 (27.4)
	7	1,974.5 (29.0)	2.0 (1.0, 2)	29,310 (17.0)	18.3 (17.0)	910 (17.0)	2.75 (16.5)
MDDPI
1,200 µg BID (N=9)	1	547 (19.3)	3.0 (1.0, 6)	5,097 (22.5)
	14	3,652 (48.9)	1.6 (1.0, 3)	34,002 (50.7)	28.3 (50.7)	588 (50.7)a	6.66 (38.4)
2,000 µg BID (N=9)	1	928 (32.8)	1.5 (1.5, 4)	8,142 (34.4)
	14	5,447 (39.3)	1.5 (1.0, 3)	51,139 (39.0)	25.6 (39.0)	652 (39.0)	6.28 (19.5)
2,400 µg BID (N=9)	1	1,230 (33.3)	3.0 (1.5, 4)	11,633 (31.7)
	14	6,922 (34.1)a	2.3 (1.0, 3)a	61,909 (37.0)a	25.8 (37.0)	646 (37.0)a	5.47 (36.6)a

Notes:

* 0–24 hours calculated for OD regimens and 0–12 hours calculated for BID regimens.

** Calculated as AUC0–24 h divided by total daily dose for Study 1 and AUC_{0–12 h} divided by half of the total daily dose in Study 2. Data are geometric mean (% coefficient of variation), except t_max which is median (range). PK population is defined as all subjects in the safety population who had at least one valid PK measurement and who had no major PK-related protocol deviations.

a n=8.

Abbreviations: AUC0–12 h, area under the curve from administration to 12 post-dose; AUC0–24 h, area under the curve from administration to 24 hours post-dose; BID, twice daily; CL/F, clearance adjusted for absolute bioavailability; C_max, maximum plasma concentration; MDDPI, study medication administered via multi-dose dry-powder inhaler; OD, once-daily; PK, pharmacokinetics; R_acc, accumulation ratio; SDDPI, study medication administered via single-dose dry-powder inhaler; t_max, time to maximum concentration.

Figure 2 CHF6001 plasma pharmacokinetic–time profile following multiple OD administration via SDDPI (PK population).

Notes: Data are mean. PK population is defined as all subjects in the safety population who had at least one valid PK measurement and who had no major PK-related protocol deviations.

Abbreviations: PK, pharmacokinetics; OD, once daily; SDDPI, study medication administered via single-dose dry-powder inhaler.

Figure 3 CHF6001 plasma pharmacokinetic–time profile following multiple BID administration via MDDPI (PK population).

Notes: Data are mean. PK population is defined as all subjects in the safety population who had at least one valid PK measurement and who had no major PK-related protocol deviations.
Abbreviations: BID, twice daily; MDDPI, study medication administered via multi-dose dry-powder inhaler; PK, pharmacokinetics.

Table 4 CHF6001 derived pharmacokinetic parameters following OD or BID administration via MDDPI

CHF6001 dose	Pharmacokinetic parameter
	Fluctuation %	Cmax,ss pg/mL	Cmin,ss pg/mL	AUC0–24 h,ss pg.h/mL
BID
150 µg	44.1 (28.8)	442 (34.1)	279 (39.9)	8,555 (35.8)
300 µg	42.8 (28.2)	880 (34.4)	563 (39.1)	17,111 (35.8)
600 µg	42.5 (28.1)	1,758 (34.4)	1,129 (38.9)	34,222 (35.8)
1,200 µg	42.4 (28.0)	3,515 (34.5)	2,259 (38.8)	68,444 (35.8)
2,400 µg	42.4 (28.0)	7,028 (34.5)	4,519 (38.8)	136,885 (35.8)
OD
2,400 µg	65.1 (27.1)	3,969 (31.9)	2,064 (39.0)	68,259 (35.1)

Notes: Simulation of data from 100 subjects replicated 10 times. Data are geometric mean (% coefficient of variation).

Abbreviations: AUC_{0–24 h,ss}, area under the curve from administration to 24 h post-dose at steady state; BID, twice daily; C_max,ss, maximum plasma concentration at steady state; C_min,ss, minimum plasma concentration at steady state; MDDPI, study medication administered via multi-dose dry-powder inhaler; OD, once daily.

Figure 4 Plasma concentration of CHF6001 following BID administration via MDDPI: simulation of data from 100 subjects replicated 10 times.

Abbreviations: BID, twice daily; MDDPI, study medication administered via multi-dose dry-powder inhaler.

Figure 5 Plasma concentration of CHF6001 following OD or BID administration of the same total daily dose via MDDPI: simulation of data from 100 subjects replicated 10 times.

Abbreviations: BID, twice daily; MDDPI, study medication administered via multi-dose dry-powder inhaler; OD, once daily.

Table 5 Number (%) of subjects reporting AEs and SAEs following administration of single doses (safety population)

	Study 1 (SDDPI)								Study 2 (MDDPI)
	Placebo (N=14)	CHF6001							Placebo (N=9)	CHF6001
		20 µg (N=8)	100 µg (N=8)	200 µg (N=8)	400 µg (N=7)	800 µg (N=7)	1,600 µg (N=7)	2,000 µg (N=6)		2,400 µg (N=9)	4,000 µg (N=8)	4,800 µg (N=8)
At least one AE	3 (21.4)	1 (12.5)	0	3 (37.5)	2 (28.6)	3 (42.9)	2 (28.6)	0	2 (22.2)	3 (33.3)	1 (12.5)	1 (12.5)
Severe AE	0	0	0	0	0	0	0	0	0	1 (11.1)	0	0
At least one SAE	0	0	0	0	0	0	0	0	0	0	0	0
AE considered related to study medication	0	0	0	0	0	0	0	0	0	1 (11.1)	1 (12.5)	0
AE leading to withdrawal	0	0	0	1 (12.5)	0	0	0	0	0	1 (11.1)	0	0
AE leading to death	0	0	0	0	0	0	0	0	0	0	0	0

Note: Safety population is defined as all randomized subjects who had received at least one dose of study medication.

Abbreviations: AE, adverse event; MDDPI, study medication administered via multi-dose dry-powder inhaler; SAE, serious adverse event; SDDPI, study medication administered via single-dose dry-powder inhaler.

Table 6 Number (%) of subjects reporting AEs and SAEs following administration of multiple doses (safety population)

	Study 1 (SDDPI)						Study 2 (MDDPI)
	Placebo (N=13)	CHF6001					Placebo (N=9)	CHF6001
		100 µg OD (N=8)	300 µg OD (N=8)	600 µg OD (N=9)	1,200 µg OD (N=9)	1,600 µg OD (N=7)		1,200 µg BID (N=9)	2,000 µg BID (N=9)	2,400 µg BID (N=9)
At least one AE	5 (38.5)	3 (37.5)	2 (25.0)	5 (55.6)	2 (22.2)	3 (42.9)	2 (22.2)	6 (66.7)	5 (55.6)	7 (77.8)
AEs occurring in more than two subjects with any treatment
Back pain	0	0	0	0	0	0	1 (11.1)	0	3 (33.3)	5 (55.6)
Headache	2 (15.4)	0	0	2 (22.2)	0	0	1 (11.1)	3 (33.3)	2 (22.2)	2 (22.2)
Severe AE	0	0	0	0	0	0	0	0	1 (11.1)	0
At least one SAE	0	0	0	0	0	0	0	0	0	0
AE considered related to study medication	2 (15.4)	0	0	0	0	0	1 (11.1)	4 (44.4)	2 (22.2)*	1 (11.1)
Headache	1 (7.7)	0	0	0	0	0	1 (11.1)	3 (33.3)	2 (22.2)	1 (11.1)
Parosmia	1 (7.7)	0	0	0	0	0	0	0	0	0
Diarrhea	0	0	0	0	0	0	0	1 (11.1)	0	0
Flatulence	0	0	0	0	0	0	0	1 (11.1)	0	0
Nausea	1 (7.7)	0	0	0	0	0	0	0	0	0
AE leading to withdrawal	0	0	0	0	0	0	0	0	0	1 (11.1)
AE leading to death	0	0	0	0	0	0	0	0	0	0

Notes:

* One subject had raised ALT values that were initially recorded as a mild AE and assessed as related; the ALT levels subsequently increased further, and although this was then considered a severe AE, it was reassessed as not related. Safety population is defined as all randomized subjects who had received at least one dose of study medication.

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; BID, twice daily; MDDPI, study medication administered via multi-dose dry-powder inhaler; OD, once daily; SAE, serious adverse event; SDDPI, study medication administered via single-dose dry-powder inhaler.

Data availability

The data of this study are available on request, following submission of a valid research protocol to the corresponding author.