Improved bioavailability of cromolyn sodium using inhaled PA101 delivered via eFlow® nebulizer

Figures & data

Table 1. Summary of pharmacokinetic parameters following administration of cromolyn sodium to healthy volunteers in study Part 1; in patients with indolent systemic mastocytosis (ISM) in study Part 2 and in patients with allergic asthma in study Part 3.

Study Part 1
Treatment		N		Cmax, ng/mL^a	Tmax, h^b	AUC0-inf, h·ng/mL^a		t½, h^a
Treatment A		12		Not measured	Not measured	Not measured		Not measured
Treatment B		12		156 (104)	0.80 (0.55, 0.82)	338 (146)		2.24 (0.602)
Treatment C		12		236 (124)	0.61 (0.57, 0.88)	526 (198)		2.05 (0.532)
Treatment D		12		88.6 (45.5)	0.53 (0.52, 0.80)	212 (96.0)		2.50 (0.717)
Treatment E		12		17.8 (10.4)	0.56 (0.55, 0.82)	40.6 (15.6)		2.50 (0.781)
Treatment F		12		5.23 (3.08)	4.00 (0.75, 8.02)	33.3 (11.7)		4.33 (1.26)
Study Part 2
Treatment	N		Cmax, ng/mL^a	Tmax, h^b	AUC0-6 h, h·ng/mL^a	AUC0-12 h, h·ng/mL^a	AUC0-inf, h·ng/mL^a		t½, h^a
Treatment B/first dose	5		102 (48.4)	0.55 (0.32–0.57)	194 (65.0)
Treatment B/second dose	5		90.0 (32.2)	0.57 (0.30–0.57)	205 (56.9)
Treatment B/third dose	5		91.2 (45.2)	0.32 (0.23–0.55)	188 (85.6)	207 (87.2)	211 (86.2)		2.29 (0.561)
Treatment F/first dose	5		5.02 (1.84)	2.00 (0.75–2.00)	19.3 (6.52)
Treatment F/second dose	5		7.32 (5.24)	1.00 (1.00–4.00)	29.8 (16.0)
Treatment F/third dose	5		10.1 (9.19)	0.50 (0.17–2.00)	37.9 (26.6)	58.1 (31.3)	80.0 (44.1)		5.04 (0.869)
Study Part 3
	N		Cmax, ng/mL^a	Tmax, h^b	AUC0-6 h, h·ng/mL^a	AUC0-12 h, h·ng/mL^a	AUC0-inf, h·ng/mL^a		t½, h^a
Treatment B/first dose	6		136 (55.0)	0.56 (0.55–0.80)	254 (80.2)
Treatment B/second dose	6		151 (85.7)	0.56 (0.53–0.81)	269(133)
Treatment B/third dose	6		112 (66.3)	0.56 (0.55–0.80)	227 (140)	266 (167)	278 (179)		2.84 (0.647)
Treatment E/first dose	6		17.3 (6.83)	0.56 (0.15–0.80)	29.7 (8.61)
Treatment E/second dose	6		16.6 (8.65)	0.80 (0.15–1.06)	32.0 (9.06)
Treatment E/third dose	6		20.7 (12.5)	0.56 (0.15–0.81)	34.7 (14.4)	40.5 (15.1)	42.5 (15.0)		3.89 (1.89)

^a: Median (min, max); ^b Mean (SD). AUC_0-inf: Area Under the Plasma Concentration-Time Curve From Time = 0 to Infinity. AUC_0-6 h: Area Under the Plasma Concentration-Time Curve From Time = 0 to 6 hours. AUC_0-12 h: Area Under the Plasma Concentration-Time Curve From Time = 0 to 12 hours. C_max: Maximum Measured Plasma Concentration. T_max: Time of Maximum Measured Cromolyn Sodium Plasma Concentration. T_1/2: Half-life.

Treatment A: Placebo. Treatment B: 40 mg PA101 (4% cromolyn sodium, 40 mg/1 mL), oral inhalation via eFlow® 30 L. Treatment C: 80 mg PA101 (4% cromolyn sodium, 80 mg/2 mL), oral inhalation via eFlow® 30 L. Treatment D: 40 mg PA101 (4% cromolyn sodium, 40 mg/1 mL), oral inhalation via eFlow® 40 L. Treatment E: 20 mg Intal^TM nebulizer solution (1% cromolyn sodium, 20 mg/2 mL), oral inhalation via LC® Plus, Treatment F: 200 mg Nalcrom® oral concentrate (cromolyn sodium 100 mg/5 mL), oral administration.

Table 2. Summary of adverse events recorded during study Part 1, Part 2 and Part 3.

Preferred term	Study Part 1						Study Part 2		Study Part 3
	Placebo (N = 12) n %	PA101			Intal^TM 20 mg (LC® Plus) N = 12 n %	Nalcrom® 200 mg (oral) N = 12 n %	PA101 40 mg (30 L) N = 5 n %	Nalcrom® 200 mg (oral) N = 5 n %	PA101 40 mg (30 L) N = 6 n %	Intal^TM 20 mg (LC® Plus) N = 5 n %
		40 mg (30 L) N = 12 n %	80 mg (30 L) N = 12 n %	40 mg (40 L) N = 12 n %
Number of subjects with at least one AE	2 (16.7)	3 (25.0)	4 (33.3)	2 (16.7)	3 (25.0)	2 (16.7)	5 (100.0)	5 (100.0)	5 (83.3)	5 (100.0)
Cough	1 (8.3)	0	1 (8.3)	1 (8.3)	1 (8.3)	0	3 (60.0)	1 (20.0)	1 (16.7)	1 (20.0)
Dyspnea	0	0	0	0	0	0	2 (40.0)	0	2 (33.3)	2 (40.0)
Throat irritation	0	0	0	0	0	0	4 (80.0)	0	3 (50.0)	3 (60.0)
Dizziness	0	2 (16.7)	0	0	0	0	0	0	2 (33.3)	1 (20.0)
Headache	0	0	1 (8.3)	0	0	1 (8.3)	2 (40.0)	1 (20.0)	3 (50.0)	1 (20.0)
Dysgeusia	0	0	0	0	0	1 (8.3)	1 (20.0)	4 (80.0)	0	0

Adverse events recorded as Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA)

Figure 1. Plasma cromolyn sodium concentrations and mean PK parameters.

(a): following three single doses of PA101 (40 or 80 mg), Nalcrom®, or Intal^TM in 12 healthy volunteers (Part 1); (b): following three doses of PA101 and Nalcrom® in patients with indolent systemic mastocytosis (Part 2); (c): following three doses of PA101 and Intal^TM in patients with allergic asthma (Part 3). The rapid rise after eFlow® PA101 drug delivery in systemic plasma concentrations is suggestive of pulmonary absorption rather than gastrointestinal absorption.Treatment B: 40 mg PA101 (4% cromolyn sodium, 40 mg/1 mL), oral inhalation via eFlow® 30 L. Treatment C: 80 mg PA101 (4% cromolyn sodium, 80 mg/2 mL), oral inhalation via eFlow® 30 L. Treatment D: 40 mg PA101 (4% cromolyn sodium, 40 mg/1 mL), oral inhalation via eFlow® 40 L. Treatment E: 20 mg Intal^TM nebulizer solution (1% cromolyn sodium, 20 mg/2 mL), oral inhalation via LC® Plus, Treatment F: 200 mg Nalcrom® oral concentrate (cromolyn sodium 100 mg/5 mL), oral administration.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.