Study on bioequivalence evaluation of daclatasvir hydrochloride tablets in healthy Chinese subjects

doi:10.12092/j.issn.1009-2501.2026.01.006

Abstract

Abstract:

AIM: To evaluate the bioequivalence and safety of the test formulation of daclatasvir hydrochloride tablets and the reference formulation of daclatasvir hydrochloride tablets (DAKLINZA^TM) in healthy Chinese subjects. METHODS: A single-dose, randomized, open-label, two-cycle, double-crossover design was used, and 60 healthy subjects were enrolled. The subjects were randomly divided into two groups, with 30 subjects in the fasting group and 30 subjects in the fed group. In the first cycle, one tablet (60 mg) of the test or reference formulation was taken orally as a single dose, and cross-administration was conducted on the 8th day. RESULTS: The main pharmacokinetic parameters of the test and reference formulations of daclatasvir hydrochloride tablets in the fasting group were as follows: C_max (1 102.690±311.345) and (1 174.800±361.642) ng/mL; AUC_0-t (13 517.051±3 576.349) and (13 503.448±4 022.914) h·ng·mL^?1; AUC_0-∞ (13 672.052±3 626.297) and (13 669.602±4 059.563) h·ng·mL^?1. The main pharmacokinetic parameters of the test and reference formulations of daclatasvir hydrochloride tablets in the fed group were as follows: C_max (791.733±230.334) and (872.000±303.921) ng/mL; AUC_0-t (10 974.708±3 213.564) and (11 217.253±4 060.319) h·ng·mL^?1; AUC_0-∞ (11 140.018±3 261.934) and (11 396.162±4 143.077) h·ng·mL^?1. The 90% confidence intervals for the geometric mean ratios of the main pharmacokinetic parameters (C_max, AUC_0-t and AUC_0-∞) of daclatasvir in plasma after oral administration of 60 mg of the test and reference formulations of daclatasvir hydrochloride tablets under fasting and fed conditions fell within the 80.00%–125.00% equivalence interval. There were no serious adverse events in both groups. CONCLUSION: The test and reference formulations of daclatasvir hydrochloride tablets were determined to be bioequivalent and safe under fasting or fed conditions.

Key words: daclatasvir hydrochloride tablets, pharmacokinetics, bioequivalence

CLC Number:

R969.1

Jing XIE, Xiaoni WANG, Jie MIN, Min LIU, Xu ZHU, Wang HU, Chang LU, Ran ZHANG, Huan ZHOU, Jian GONG. Study on bioequivalence evaluation of daclatasvir hydrochloride tablets in healthy Chinese subjects[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(1): 55-62.

Figures/Tables 7

References 20

1	Bernal LA, Soti V. Hepatitis C virus: Insights into its history, treatment, challenges, and future directions[J]. Cureus, 2023, 15 (8): e43924. doi: 10.7759/cureus.43924
2	Martinello M, Solomon SS, Terrault NA, et al. Hepatitis C[J]. Lancet, 2023, 402 (10407): 1085- 1096. doi: 10.1016/S0140-6736(23)01320-X
3	Fiehn F, Beisel C, Binder M. Hepatitis C virus and hepatocellular carcinoma: carcinogenesis in the era of direct-acting antivirals[J]. Curr Opin Virol, 2024, 67, 101423. doi: 10.1016/j.coviro.2024.101423
4	Manns MP, Maasoumy B. Breakthroughs in hepatitis C research: from discovery to cure[J]. Nat Rev Gastroenterol Hepatol, 2022, 19 (8): 533- 550. doi: 10.1038/s41575-022-00608-8
5	Polaris Observatory HCV Collaborators. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study[J]. Lancet Gastroenterol Hepatol, 2022, 7 (5): 396- 415. doi: 10.1016/S2468-1253(21)00472-6
6	常宇琨, 章志丹. 《丙型肝炎防治指南(2022版)》更新解读[J]. 新发传染病电子杂志, 2023, 8 (6): 89- 92. doi: 10.3760/cma.j.cn501113-20230529-00233
7	周梅, 姚丽熙, 吴银莲, 等. 1990—2044年中国丙型病毒性肝炎相关疾病的疾病负担分析及预测[J]. 中国血吸虫病防治杂志, 2023, 35 (5): 476- 485. doi: 10.16250/j.32.1374.2023059
8	Sabry N, Kamel AM, Cordie A, et al. Daclatasvir as a hepatitis C infection treatment option: an up-to-date evaluation[J]. Expert Opin Pharmacother, 2023, 24 (2): 159- 170. doi: 10.1080/14656566.2022.2145883
9	European Medicines Agency. Daklinza: EPAR-Product Information [EB/OL]. (2014-09-15)[2019-08-22]. https://www.ema.europa.eu/en/medicines/human/EPAR/daklinza#ema-inpage-item-overview.
10	Keating GM. Daclatasvir: a review in chronic hepatitis C[J]. Drugs, 2016, 76 (14): 1381- 1391. doi: 10.1007/s40265-016-0632-x
11	国家药品监督管理总局. 总局批准盐酸达拉他韦片和阿舒瑞韦软胶囊上市[EB/OL]. [2024-04-07]. https://www.nmpa.gov.cn/yaopin/ypjgdt/20170428101301734.html.
12	World Health Organization (WHO). The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO model list of essential medicines and the 7th WHO model list of essential medicines for children) [EB/OL]. [2024-04-07]. https://iris.who.int/handle/10665/330668.
13	Irekeola AA, Ear ENS, Mohd Amin NAZ, et al. Antivirals against HCV infection: the story thus far[J]. J Infect Dev Ctries, 2022, 16 (2): 231- 243. doi: 10.3855/jidc.14485
14	Alqahtani SA, Sulkowski MS. Chronic hepatitis C: Advances in therapy and the remaining challenges[J]. Med Clin North Am, 2023, 107 (3): 423- 433.
15	Ioannou GN, Feld JJ. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection ?[J]. Gastroenterology, 2019, 156(2): 446-460. e2.
16	Guidelines for the Care and Treatment of Persons Diagnosed with Chronic Hepatitis C Virus Infection [M]. Geneva: World Health Organization, 2018 Jul.
17	郝竟琳, 韩杰, 付萌萌, 等. 盐酸达拉他韦片及阿舒瑞韦软胶囊联合用药治疗丙型肝炎的分析探讨[J]. 首都食品与医药, 2018, 25 (15): 51- 52. doi: 10.3969/j.issn.1005-8257.2018.15.041
18	Gandhi Y, Eley T, Fura A, et al. Daclatasvir: A review of preclinical and clinical pharmacokinetics[J]. Clin Pharmacokinet, 2018, 57 (8): 911- 928. doi: 10.1007/s40262-017-0624-3
19	Shiozaki T, Ueno T, Nagashima H, et al. Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects[J]. Int J Clin Pharmacol Ther, 2015, 53 (4): 292- 302. doi: 10.5414/cp202186
20	Shi LP, Yang X, Liu F, et al. Bioequivalence of daclatasvir hydrochloride tablets in healthy Chinese subjects[J]. Int J Clin Pharmacol Ther, 2021, 59 (8): 585- 592. doi: 10.5414/cp203895

Items	Fasting	Fed
Gender (man/female)	25/5	25/5
Age (years)	32.07 ± 12.14	29.03 ± 9.09
Height (cm)	168.98 ± 8.65	169.52 ± 8.35
Body weight (kg)	64.90 ± 9.99	64.85 ± 8.85
BMI (kg/m²)	22.62 ± 1.92	22.52 ± 2.00
Rance (Han Chinese/Non-Han Chinese)	29/1	30/0

Items	Fasting	Fed
Gender (man/female)	25/5	25/5
Age (years)	32.07 ± 12.14	29.03 ± 9.09
Height (cm)	168.98 ± 8.65	169.52 ± 8.35
Body weight (kg)	64.90 ± 9.99	64.85 ± 8.85
BMI (kg/m²)	22.62 ± 1.92	22.52 ± 2.00
Rance (Han Chinese/Non-Han Chinese)	29/1	30/0

Conentration (ng/mL)	Intra-day ($ \overline{x} $±s, n=6, ng/mL)	CV (%)	RE (%)	Inter-day ($ \overline{x} $±s, n=18, ng/mL)	CV (%)	RE (%)	Relative recovery (%)
3.00	2.96±0.0540	1.8	?1.3	2.99±0.0849	2.8	?0.3	/
8.00	8.17±0.146	1.8	2.1	8.07±0.236	2.9	0.9	89.8
150	157±3.25	2.1	4.7	156±5.61	3.6	4.0	/
800	829±15.7	1.9	3.6	807±26.8	3.3	0.9	93.1
1500	1480±9.83	0.7	?1.3	1440±58.3	4.0	?4.0	89.5

Conentration (ng/mL)	Intra-day ($ \overline{x} $±s, n=6, ng/mL)	CV (%)	RE (%)	Inter-day ($ \overline{x} $±s, n=18, ng/mL)	CV (%)	RE (%)	Relative recovery (%)
3.00	2.96±0.0540	1.8	?1.3	2.99±0.0849	2.8	?0.3	/
8.00	8.17±0.146	1.8	2.1	8.07±0.236	2.9	0.9	89.8
150	157±3.25	2.1	4.7	156±5.61	3.6	4.0	/
800	829±15.7	1.9	3.6	807±26.8	3.3	0.9	93.1
1500	1480±9.83	0.7	?1.3	1440±58.3	4.0	?4.0	89.5

Items	Condition	Result
Plasma sample	Place at room temperature for 18.7 hours	Good
	5 freeze-thaw cycles at ?20 ℃/?70 ℃
	Freeze for 50 days at ?20 ℃/?70 ℃ for a long time
Supernatant after plasma sample processing	Place in the automatic sampler at 8 ℃ for 5 days
Stock solution	Place at room temperature for 16.2 hours
	Place at ?20 ℃ for 16 days
	Place at ?20 ℃ for 43 days
Working solution	Place at room temperature for 15.8 hours
Working solution	Place at ?20 ℃ for 15 days