The pharmacokinetics, safety, and tolerability of single, high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma

Figures & data

Figure 1. Study visits. ^*Mometasone furoate inhalation powder 220 mcg, 1 inhalation twice daily, to be used during screening and washout periods. ICS, inhaled corticosteroid.

Figure 2. Patient disposition. ^*Of the 43 enrolled patients, 3 patients withdrew consent before receiving any study drug. FAS, full analysis set; Fp DPI, fluticasone propionate dry powder inhaler; Fp MDPI, fluticasone propionate multidose dry powder inhaler; FS DPI, fluticasone propionate/salmeterol dry powder inhaler; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler; PK, pharmacokinetic analysis set.

Table 1. Patient demographics and baseline characteristics, intent-to-treat population.

Demographic variables	Total (N = 43)
Age, mean (SD), years	29.6 (17.12)
12–17 years old, n (%)	17 (40)
≥18 years old, n (%)	26 (60)
Sex, n (%)
Male	24 (56)
Female	19 (44)
Race, n (%)
White	31 (72)
Black	11 (26)
Other	1 (2)
Weight, mean (SD), kg	76.3 (14.22)
BMI, mean (SD), kg/m^2	26.3 (4.10)
Peak inspiratory flow rate, mean (SD), L/min	94.3 (12.88)
Percent-predicted FEV1, mean (SD)	87.3 (12.74)
Asthma history, n (%)
<5 years	0
5 years to <10 years	6 (14)
10 years to <15 years	15 (35)
≥15 years	22 (51)
Medical history, occurring in ≥12%, n (%)
Seasonal allergy	33 (77)
Sinus headache	12 (28)
Dry hypersensitivity	9 (21)
Tension headache	9 (21)
Eczema	8 (19)
Gastroesophageal reflux disease	6 (14)
Food allergy	5 (12)
Migraine	5 (12)
Myopia	5 (12)
Post menopause	5 (12)
Rhinitis allergic	5 (12)
Prior medication therapy, used by ≥2 patients, n (%)	43 (100)
Drugs for obstructive airway diseases	43 (100)
Antihistamines, systemic	12 (28)
Analgesics	4 (9)
Anti-diabetic medication	4 (9)
Oral contraceptives/hormone replacement therapy	4 (9)
Proton pump inhibitors	3 (7)
Lipid-modifying agents	3 (7)
Thyroid hormone replacement therapy	3 (7)
Antibacterial, systemic	2 (5)
Anti-inflammatory and anti-rheumatic	2 (5)
Antithrombotic agents	2 (5)
Nasal preparations	2 (5)

BMI, body mass index; FEV₁, forced expiratory volume in 1 s; SD, standard deviation.

Figure 3. Plasma concentration-vs-time profiles for fluticasone propionate (a) and salmeterol (b), pharmacokinetic analysis set. Fp DPI, fluticasone propionate dry powder inhaler 500 mcg; Fp MDPI, fluticasone propionate multidose dry powder inhaler 200 mcg; FS DPI, fluticasone propionate/salmeterol dry powder inhaler 500/50 mcg; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler 200/12.5 mcg.

Table 2. Fluticasone propionate plasma pharmacokinetic parameters, pharmacokinetic analysis set.

		Fp MDPI 200 mcg	Fp DPI 500 mcg	FS MDPI 200/12.5 mcg	FS DPI 500/50 mcg
Cmax, pg/mL	n	39	37	37	37
	Mean	73.0	85.5	65.8	67.1
	Geo mean	67.5	78.1	61.6	61.3
	Min, max	21.1, 158.5	21.1, 160.0	21.9, 139.1	11.2, 137.7
	CV, %	39.0	39.0	37.0	40.0
tmax, h	n	39	37	37	37
	Median	1.0	1.0	2.0	1.0
	Min, max	0.5, 4.0	0.5, 4.0	0.1, 4.0	0.3, 4.1
	CV, %	58.7	67.6	66.4	70.4
AUC0–t, h·pg/mL	n	38	37	36	37
	Mean	654.6	810.1	582.5	626.4
	Geo mean	597.2	739.0	544.7	559.9
	Min, max	120.9, 1813.5	147.5, 1750.4	162.3, 870.9	53.2, 1099.7
	CV, %	43.9	40.8	32.1	40.6
AUC0–inf, h·pg/mL	n	32	33	30	33
	Mean	709.1	875.5	626.4	687.0
	Geo mean	642.5	796.4	585.6	608.1
	Min, max	128.5, 2157.6	155.0, 1868.6	170.7, 944.0	61.0, 1186.2
	CV, %	48.8	41.0	32.2	42.6
%AUCextrap, %	n	32	33	30	33
	Mean	7.8	7.8	6.9	8.5
	Geo mean	7.4	7.3	6.7	7.8
	Min, max	3.2, 15.9	3.2, 15.1	4.3, 10.9	3.3, 14.9
	CV, %	36.8	36.3	27.0	39.9
t½, h	n	32	33	30	33
	Mean	11.3	11.0	10.8	11.3
	Geo mean	11.2	11.0	10.7	11.1
	Min, max	8.3, 14.3	7.5, 14.4	7.6, 13.9	6.8, 16.8
	CV, %	12.6	13.8	13.3	21.7

AUC_0–inf, area under the plasma concentration-time curve from time 0 to infinity; %AUC_extrap, percentage of AUC_0–inf due to extrapolation; AUC_0–t, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration; C_max, maximum observed plasma concentration; CV, coefficient of variation; Fp DPI, fluticasone propionate dry powder inhaler; Fp MDPI, fluticasone propionate multidose dry powder inhaler; FS DPI, fluticasone propionate/salmeterol dry powder inhaler; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler; Geo, geometric; t_½, terminal elimination half-life; t_max, time to maximum observed plasma concentration.

Table 3. Fluticasone propionate treatment comparisons, pharmacokinetic analysis set.

Parameter	Treatment comparison	n	Geometric LS means	Ratio of geometric LS means		90% CI of ratio	Root MSE	Intra-patient CV
Cmax, pg/mL	Fp MDPI vs	37	66.4	0.85		0.77, 0.93	—	—
	Fp DPI	37	78.3				—	—
	FS MDPI vs	36	61.9	1.01		0.92, 1.10	—	—
	FS DPI	36	61.6				—	—
	Fp MDPI vs	37	66.5	1.09		0.99, 1.19	0.236	0.239
	FS MDPI	37	61.2
AUC0–t,	Fp MDPI vs	37	593.3	0.80		0.72, 0.88	—	—
h·pg/mL	Fp DPI	37	744.0				—	—
	FS MDPI vs	36	545.5	0.96		0.87, 1.07	—	—
	FS DPI	36	567.0				—	—
	Fp MDPI vs	36	593.2	1.09		0.98, 1.21	0.268	0.273
	FS MDPI	36	544.8
AUC0–inf,	Fp MDPI vs	30	616.5	0.76		0.69, 0.83	—	—
h·pg/mL	Fp DPI	30	812.9				—	—
	FS MDPI vs	28	586.9	0.95		0.86, 1.04	—	—
	FS DPI	28	618.5				—	—
	Fp MDPI vs	25	623.6	1.07		0.96, 1.19	0.225	0.228
	FS MDPI	25	583.7
							Point estimate
						Treatment	of the	90% CI of the
Parameter	Treatment	n	Median	Min	Max	comparison	difference	difference
tmax, h	Fp MDPI	39	1.0	0.5	4.0	Fp MDPI/Fp DPI	0.000	−0.375, 0.225
	Fp DPI	37	1.0	0.5	4.0
	FS MDPI	37	2.0	0.1	4.0	FS MDPI/FS DPI	0.008	0.000, 0.375
	FS DPI	37	1.0	0.3	4.1
t½, h	Fp MDPI	32	11.4	8.3	14.3	Fp MDPI/Fp DPI	0.181	−0.342, 0.771
	Fp DPI	33	10.7	7.5	14.4
	FS MDPI	30	10.7	7.6	13.9	FS MDPI/FS DPI	−0.055	−0.650, 0.462
	FS DPI	33	10.7	6.8	16.8

AUC_0–inf, area under the plasma concentration-time curve from time 0 to infinity; AUC_0–t, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration; CI, confidence interval; C_max, maximum observed plasma concentration; CV, coefficient of variation; Fp DPI, fluticasone propionate dry powder inhaler; Fp MDPI, fluticasone propionate multidose dry powder inhaler; FS DPI, fluticasone propionate/salmeterol dry powder inhaler; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler; LS, least square; MSE, mean square error; t_½, terminal elimination half-life; t_max, time to maximum observed plasma concentration.

Table 4. Salmeterol plasma pharmacokinetic parameters, pharmacokinetic analysis set.

		FS MDPI 200/12.5 mcg	FS DPI 500/50 mcg
Cmax, pg/mL	n	38	35
	Mean	60.1	81.1
	Geo mean	54.3	68.5
	Min, max	16.5, 123.4	20.0, 197.4
	CV, %	42.7	56.6
tmax, h	n	38	35
	Median	0.1	0.1
	Min, max	0.1, 0.8	0.1, 2.0
	CV, %	105.4	166.6
AUC0–t, h·pg/mL	n	37	35
	Mean	125.3	271.3
	Geo mean	118.1	241.1
	Min, max	47.9, 265.3	95.3, 763.8
	CV, %	36.0	55.3
AUC0–inf, h·pg/mL	n	36	35
	Mean	141.2	297.1
	Geo mean	133.3	264.7
	Min, max	57.3, 298.9	104.2, 837.4
	CV, %	35.8	54.3
%AUCextrap, %	n	36	35
	Mean	11.0	8.8
	Geo mean	10.7	8.2
	Min, max	6.2, 17.8	2.5, 14.3
	CV, %	24.3	36.2
t½, h	n	36	35
	Mean	12.6	12.1
	Geo mean	12.5	11.9
	Min, max	10.8, 16.0	8.1, 16.9
	CV, %	12.5	18.9

AUC_0–inf, area under the plasma concentration-time curve from time 0 to infinity; %AUC_extrap, percentage of AUC_0–inf due to extrapolation; AUC_0–t, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration; C_max, maximum observed plasma concentration; CV, coefficient of variation; FS DPI, fluticasone propionate/salmeterol dry powder inhaler; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler; Geo, geometric; t_½, terminal elimination half-life; t_max, time to maximum observed plasma concentration.

Table 5. Salmeterol treatment comparisons, pharmacokinetic analysis set.

Parameter	Treatment comparison		n	Geometric LS means			Ratio of geometric LS means	90% CI of ratio
Cmax, pg/mL	FS MDPI vs FS DPI		35	56.5			0.81	0.70, 0.94
			35	69.7
AUC0–t, h·pg/mL	FS MDPI vs FS DPI		35	119.7			0.50	0.46, 0.54
			35	241.2
AUC0–inf, h·pg/mL	FS MDPI vs FS DPI		34	134.4			0.51	0.47, 0.55
			34	262.7
Parameter	Treatment	n	Median	Min	Max	Treatment comparison	Point estimate of the difference	90% CI of the difference
tmax, h	FS MDPI	38	0.1	0.1	0.8	FS MDPI/FS DPI	0.000	−0.333, 0.000
	FS DPI	35	0.1	0.1	2.0
t½, h	FS MDPI	36	12.6	10.8	16.0	FS MDPI/FS DPI	0.207	−0.350, 0.856
	FS DPI	35	11.8	8.1	16.9

AUC_0–inf, area under the plasma concentration-time curve from time 0 to infinity; AUC_0–t, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration; CI, confidence interval; C_max, maximum observed plasma concentration; FS DPI, fluticasone propionate/salmeterol dry powder inhaler; FS MDPI, fluticasone propionate/salmeterol multidose dry powder inhaler; LS, least square; t_½, terminal elimination half-life; t_max, time to maximum observed plasma concentration.