Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

Figures & data

Table 1 Adhesion score and skin irritation score systems in this study

Adhesion score	Extent of adhesion
0	≥90% adhesion
1	≥75% to <90% adhesion
2	≥50% to <75% adhesion
3	<50% adhesion but patch not detached
4	Patch detached
Skin irritation score	Extent of irritation
0	No evidence of irritation
1	Minimal erythema
2	Definite erythema, minimal edema or minimal papular response
3	Erythema and papules
4	Definite edema
5	Erythema, edema, and papules
6	Vesicular eruption
7	Strong reaction spread beyond test site

Table 2 Pharmacokinetic parameters of donepezil

	Donepezil dose
	43.75 mg/12.5 cm^2 (n=9)	87.5 mg/25 cm^2 (n=9)	175 mg/50 cm^2 (n=9)
AUClast (ng·h/mL)	716.82±427.94	1,600.24±408.48	2,574.32±899.07
AUCinf (ng·h/mL)	808.52±474.05	1,762.42±431.95	2,761.15±889.71
AUCinf/dose (ng·h/mL/mg)	18.48±10.84	20.14±4.94	15.78±5.08
Cmax (ng/mL)	5.24±3.43	13.00±5.45	20.36±7.43
Cmax/dose (ng/mL/mg)	0.12±0.08	0.15±0.06	0.12±0.04
t1/2β (hours)	94.07±19.61	75.52±15.44	63.77±11.27
CL/F (L/h)	72.28±38.00	52.31±12.47	70.49±25.73
tmax (hours)	76.0 (70.0, 95.9)	76.0 (74.0, 119.2)	74.0 (70.0, 119.2)

Notes: Data are presented as mean ± standard deviation, except for t_max, which is expressed as median (minimum, maximum).

Abbreviations: n, number of subjects; AUC_last, area under the plasma concentration–time curve from time 0 to last measurable time point; AUC_inf, area under the plasma concentration–time curve from time 0 to infinity; C_max, measured peak plasma concentration; t_1/2β, terminal half-life; CL/F, oral clearance; t_max, time to reach peak concentration.

Table 3 Patch adhesion scores during 72-hour donepezil patch administration

Hours after patch administration	Donepezil dose
	43.75 mg/12.5 cm^2 (n=9)	87.5 mg/25 cm^2 (n=9)	175 mg/50 cm^2 (n=9)
0	0 (0, 0)	0 (0, 0)	0 (0, 0)
12	0 (0, 0)	0 (0, 0)	0 (0, 0)
24	0 (0, 0)	0 (0, 0)	0 (0, 1)
36	0 (0, 0)	0 (0, 1)	0 (0, 1)
48	0 (0, 1)	0 (0, 1)	0 (0, 1)
60	0 (0, 1)	0 (0, 2)	0 (0, 1)
72	0 (0, 1)	0 (0, 4)	0 (0, 2)

Notes: Data are presented as median (minimum, maximum). Under “Hours after patch administration”, the value 0 indicates the point at which the patch was attached.

Abbreviation: n, number of subjects.

Figure 1 Plasma concentration-time curves of donepezil 72 hour after patch application.

Notes: Data points are expressed as mean ± standard deviation. Patch was applied at hour 0.

Figure 2 Box-Whisker plots of donepezil pharmacokinetics in subjects 72 hours after patch application.

Notes: Box-Whisker plots of C_max/dose for donepezil (A) and of AUC_inf/dose for donepezil (B) 72 hours after application of the donepezil patch. The box edges indicate the minimum and the maximum values of each parameter. The whiskers extend from the 25th and 75th quartiles, and the line in the middle indicates the median value.
Abbreviations: AUC_inf, area under the plasma concentration–time curve from time 0 to infinity; AUC_inf/dose, dose-normalized area under the plasma concentration–time curve from time 0 to infinity; C_max, measured maximum plasma concentration; C_max/dose, dose-normalized measured maximum plasma concentration.

Table 4 Summary of AEs and causal relationship after donepezil patch administration

Type of AE	Placebo (n=9)	Donepezil patch dose
		43.75 mg/12.5 cm^2 (n=9)		87.5 mg/25 cm^2 (n=9)		175 mg/50 cm^2 (n=9)
	All AEs	All AEs	Drug-related AEs	All AEs	Drug-related AEs	All AEs	Drug-related AEs
Total	2 (3)	3 (3)	1 (1)	2 (2)	2 (2)	4 (6)	3 (5)
Hypertriglyceridemia	1 (1)	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Nasal stuffiness	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Rhinorrhea	1 (1)	0 (0)	0(0)	0 (0)	0 (0)	0 (0)	0 (0)
Diarrhea	0 (0)	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Papules on patch adhesion site	0 (0)	1 (1)	1 (1)	0 (0)	0 (0)	0 (0)	0 (0)
Skin discoloration, patch adhesion site	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)	0 (0)	0 (0)
Bilirubin total increased	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)	0 (0)	0 (0)
Ankle sprain	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	0 (0)
Headache	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)
Abdominal discomfort	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)
Upper abdominal discomfort	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)
Nausea	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)
Vomiting	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (1)	1 (1)

Note: Data are presented as n (number of events).

Abbreviations: AE, adverse event; n, number of subjects.

Figure 3 Distribution of individual skin irritation scores after removal of the donepezil patch.

Notes: Data are for irritation scores assessed at these times: the time of patch removal, which was 72 hours after patch application (A); 1 hour after patch removal, which was 73 hours after patch application (B) 12 hours after patch removal, which was 84 hours after patch application (C); 24 hours after patch removal, which was 96 hours after patch application (D). The scores are defined as follows: 0, no evidence of irritation; 1, minimal erythema; 2, definite erythema, readily visible; 3, erythema and papules.