Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

Yewon Choi; Su-jin Rhee; In-Jin Jang; Kyung-Sang Yu; Sung-Vin Yim; Bo-Hyung Kim

doi:10.12793/tcp.2015.23.1.26

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Choi, Rhee, Jang, Yu, Yim, and Kim: Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

Original Article

Translational and Clinical Pharmacology 2015;23(1):26-30.

Published online: 30 June 2015

DOI: https://doi.org/10.12793/tcp.2015.23.1.26

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

Yewon Choi¹, Su-jin Rhee¹, In-Jin Jang¹, Kyung-Sang Yu¹, Sung-Vin Yim², Bo-Hyung Kim^2,^∗

¹Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 110–744, Korea

²Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul 130–872, Korea

^∗Correspondence: B. H. Kim; Tel: +82-2-958-9326, Fax: +82-2-958-9559, E-mail: bhkim98@khu.ac.kr

Received 14 May 2015 Revised 4 June 2015 Accepted 5 June 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Donepezil is a centrally acting, reversible acetylcholinesterase inhibitor that is widely used for treating Alzheimer's disease. This study aimed to compare the pharmacokinetics of Bastia®, a test tablet formulation of donepezil hydrochloride 10 mg, with those of Aricept®, the reference tablet formulation of donepezil hydrochloride 10 mg, in healthy Korean male volunteers. A randomized, single-dose, two-way crossover study was conducted in 32 subjects. Subjects received a single dose of either test or reference compound and the alternate drug after a 4-week washout period. Serial blood samples for pharmacokinetic analysis were collected prior to dosing and periodically for 288 h after dosing for measurement of the plasma concentrations of donepezil. A non-compartmental method was used to estimate the pharmacokinetic parameters. The maximum concentration (C_max) and the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC_288h) for the two formulations were compared to evaluate bioequivalence. The C_max of the test and reference drugs were 27.58±7.46 and 26.35±6.51 μg/L (mean±SD), respectively, while AUC_288h was 1080.14±229.77 and 1043.07±242.28 μg·h/L (mean±SD), respectively. The geometric mean ratios (90% confidence interval) of the C_max and AUC_288h of the two tablets were 1.043 (0.990–1.099) and 1.039 (1.013–1.065). In conclusion, the newly formulated tablet of donepezil hydrochloride 10 mg is bioequivalent to the currently marketed 10 mg tablet.

Keywords: Bioequivalence, Pharmacokinetics, Donepezil

References

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Figure 1.

Mean plasma concentration-time profiles of donepezil after single oral administration of reference formulation (filled circles) and test formulation (open circles). Bars represent standard deviations. (Left, linear; right, log-linear)

Figure 2.

Individual subject's C_max and AUC_288h values for donepezil reference formulation and test formulation (Left: AUC_288h, Right: C_max)

Table 1.

Pharmacokinetic parameters of donepezil administered as the reference drug and test formulation

Parameters	Reference (N=25)		Test (N=25)
Parameters	Mean±SD	CV(%)	Mean±SD	CV(%)	Geometric mean ratio (90% CI)^b
t_max (h)^a	2.0 (1.0–4.0)		2.0 (1.5–3.0)
C_max (μg/L)	26.35±6.51	24.71	27.58±7.46	27.04	1.043 (0.990–1.099)
AUC_144h (μg·h/L)	867.37±188.69	21.75	897.97±180.10	20.06	1.035 (1.010–1.062)
AUC_240h (μg·h/L)	1008.30±230.20	22.83	1044.24±218.32	20.91	1.039 (1.013–1.064)
AUC_288h (μg·h/L)	1043.07±242.28	23.23	1080.14±229.77	21.27	1.039 (1.013–1.065)
AUC_inf (μg·h/L)	1108.44±268.52	24.23	1143.71±254.17	22.22	1.035 (1.009–1.061)
AUCextra_144h^a (%)	20.37 (13.97–29.33)		21.98 (13.46–30.86)
AUCextra_240h ^a (%)	8.38 (4.80–15.25)		8.59 (4.51–13.53)
AUCextra_288h^a (%)	5.26 (2.73–10.88)		5.30 (2.55–8.59)
Half-life (h)	72.81±11.78	16.18	70.4±10.08	14.31
CL/F (L/h)	9.65±2.87	29.77	9.27±2.63	28.42

All values, except for AUCextra_144h, AUCextra_240h and AUCextra_288h, are presented as the arithmetic mean±standard deviation and coefficient of variation (%). t_max, time to peak concentration; C_max, peak plasma concentration; AUC_t, area under the plasma concentration-time curve from 0 to t h; AUCextra_t(%), % extrapolated AUC_t which was calculated as [(AUC_inf-AUC_t) / AUC_inf]; CL/F, apparent clearance.

^a Median value [min – max].

^b Geometric mean ratio of test/reference, exponentiation of least square mean difference (90% CI) of logarithmic transformed C_max and AUC values.

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