Rapid Systemic Delivery of Zolmitriptan Using an Adhesive Dermally Applied Microarray

Figures & data

Figure 1. Adhesive Dermally-Applied Microarray (ADAM) with zolmitriptan-coated titanium microprojections.

Left panel depicts the assembled ADAM. Right shows a scanning electron micrograph of the zolmitriptan-coated microprojections.

Figure 2. Adhesive Dermally-Applied Microarray application.

ADAM: Adhesive Dermally-Applied Microarray.

Figure 3. Adhesive Dermally-Applied Microarray patch ring assembly.

ADAM: Adhesive Dermally-Applied Microarray.

Figure 4. Schematic of drug delivery using the Adhesive Dermally-Applied Microarray.

Figure 5. Pharmacokinetic study schema.

Table 1. Study treatments.

Part 1
Treatment A	ADAM zolmitriptan 0.48 mg
Treatment B	2 × ADAM zolmitriptan 0.48 mg (total = 0.96 mg)
Treatment C	ADAM zolmitriptan 1.9 mg
Treatment D	Zolmitriptan tablet 2.5 mg
Treatment E	Sumatriptan succinate 6.0 mg/0.5 ml for subcutaneous injection
Part 2
Treatment F	2 × ADAM zolmitriptan 1.9 mg (total = 3.8 mg)
Part 3
Treatment G	ADAM zolmitriptan 3.8 mg

ADAM:Adhesive dermally applied microarray.

Table 2. Participant demographics and baseline characteristics.

	Study (n = 20)
Gender Female, n	10
Mean (SD) age, years	29 (10)
Race, n (%)
Caucasian	18 (90)
Hispanic/latino	2 (10)
Mean (SD) BMI, kg/m^2	24 (4)

SD: Standard deviation.

Figure 6. Concentration–time curves following administration of zolmitriptan with the Adhesive Dermally-Applied Microarray or subcutaneous sumatriptan.

(A) Zolmitriptan groups A, B, C, D, F, G, zero to 24 h (B) Zolmitriptan groups A, B, C, D, F, G, zero to 2 h (C) Sumatriptan group E, zero to 24 h (D) Sumatriptan group E, zero to 2 h.

Table 3. Plasma pharmacokinetic parameters.

Treatment group	tmax (min) median (range)	t1/2 (H) mean (SD)	Cmax (ng/ml) mean (SD)	AUCinf (ng.H/ml) mean (SD)	AUC2hrs (ng.H/ml) mean (SD)	AUC0–30 min (ng.H/ml) mean (SD)	AUC0–15 min (ng.H/ml) mean (SD)	Frel AUCinf	Frel Cmax
Zolmitriptan
A	20 (2–30)^†	1.15 (0.3)^†	1.84 (0.5)^†	3.81 (1.5)^†	2.11 (0.7)^†	0.7 (0.23)^†	0.3 (0.12)^†	0.73	2.60
B	20 (2–30)	1.29 (0.3)	3.70 (1.0)	7.71 (2.0)	4.15 (1.0)	1.4 (0.39)	0.6 (0.21)	0.77	2.65
C	20 (2–30)	1.46 (0.3)	6.76 (2.8)	14.14 (4.5)	7.36 (2.5)	2.4 (1.02)	1.1 (0.52)	0.70	2.35
D	60 (30–240)	3.27 (0.8)^‡	3.77 (1.5)^†	27.19 (11.3)^‡	4.72 (2.2)^†	5.6 (1.87)	2.5 (0.76)	–	–
F	18 (2–30)	1.53 (0.3)	14.61 (4.5)	30.12 (10.1)	16.44 (5.3)	0.33 (0.34)	0.04 (0.11)	0.74	2.63
G	15 (2–30)	1.52 (0.3)	22.56 (14.0)	33.81 (8.0)	19.33 (5.4)	0.7 (0.23)	0.3 (0.12)	0.86	3.73
N-desmethyl zolmitriptan metabolite
A	60 (30–120)^‡	3.31 (1.6)^§	0.22 (0.1)^‡	1.38 (0.5)^‡	0.31 (0)‡	ND	ND	0.46	0.52
B	60 (15–90)	3.28 (1.8)	0.42 (0.1)	2.43 (0.8)	0.62 (0.2)	ND	ND	0.43	0.52
C	60 (30–90)	3.05 (1.0)	0.74 (0.3)	3.65 (1.2)	1.07 (0)	ND	ND	0.32	0.43
D	120 (60–240)^†	3.22 (1.1)^†	2.08 (0.5)^†	14.55 (3.1)^†	2.31 (0.9)^†	ND	ND	–	–
F	60 (30–90)	2.82 (0.5)	1.41 (0.5)	7.21 (2.3)	2.15 (0.7)	ND	ND	0.32	0.43
G	60 (20–90)	2.70 (0.5)	1.77 (0.6)	8.17 (2.0)	2.66 (0.8)	ND	ND	0.36	0.52

†‡§ n = 19; n = 18; n = 16.

AUC: Area under the concentration–time curve; C_max: Peak plasma concentration; ND: Not determined; SD: Standard deviation; t_1/2: Half life; t_max: Time to reach C_max.

Table 4. Intergroup pairwise comparisons of AUC_2h.

Treatment group	B	C	D	F	G
A	p < 0.0001	p < 0.0001	p = 0.0003	p < 0.0001	p < 0.0001
B		p < 0.0001	p = 0.4196	p < 0.0001	p < 0.0001
C			p = 0.0015	p < 0.0001	p < 0.0001
D				p < 0.0001	p = 0.0001
F					p = 0.0334

Table 5. Adverse events with incidence ≥1.

Number of adverse events n (%)	Treatment group
	A (n = 19)	B (n = 20)	C (n = 20)	D (n = 19)	E (n = 20)	F (n = 20)	G (n = 20)
Paresthesia	–	2 (10)	3 (5)	–	6 (30)	10 (50)	8 (40)
Headache	3 (16)	2 (10)	4 (20)	–	–	4 (20)	4 (20)
Throat and jaw tightness, heaviness, ache	–	–	1 (5)	–	–	2 (10)	2 (10)
Hot flushes	–	–	–	–	–	2 (10)	2 (10)
Lightheadedness and vasovagal response	1 (5)	–	–	–	1 (5)	–	1 (5)
Nausea	1 (5)	–	–	–	–	1 (5)	–
Neck tightness and stiffness	–	–	–	–	1 (5)	1 (5)	–
Upper respiratory tract infection	–	–	–	–	–	2 (10)	–

Table 6. Application site assessments at 30 min and 24 h after removal of the Adhesive Dermally-Applied Microarray.

Group mean score	Time postapplication
	Erythema		Edema		Punctate bruising		Bleeding
	30 min	24 h	30 min	24 h	30 min	24 h	30 min	24 h
A^†	1.11	0.74	0.47	0.05	0.11	0.00	0.79	0.00
B	1.10	0.78	0.50	0.23	0.15	0.05	0.85	0.03
C	1.30	0.95	0.85	0.10	0.55	1.20	1.35	0.00
F	1.20	0.90	1.05	0.00	1.10	0.30	1.20	0.00
G	1.35	1.00	1.50	0.00	0.50	0.00	1.85	0.00

† n = 19.

Erythema: 0 = None, 1 = Mild redness, 2 = Well-defined redness, 3 = Beet redness.

Edema: 0 = None, 1 = Slight edema, 2 = Moderate edema, 3 = Severe edema.

Punctate bruising: 0 = None, 1 = ≤25% application site(s) has punctate bruising spots, 2 = ≥26 to ≤50% application site(s) has punctate bruising spots, 3 = >50% application site(s) has punctate bruising spots.

Bleeding: 0 = None, 1 = Color on swab, 2 = Visible blood drop, 3 = Active bleeding.