多巴丝肼片在中国健康受试者中空腹和餐后条件下的生物等效性研究

doi:10.12092/j.issn.1009-2501.2026.07.005

中国临床药理学与治疗学 ›› 2026, Vol. 31 ›› Issue (7): 899-907.doi: 10.12092/j.issn.1009-2501.2026.07.005

多巴丝肼片在中国健康受试者中空腹和餐后条件下的生物等效性研究

李林¹^,²(), 夏玉明³, 沈陈林¹, 夏泉¹^,⁴, 宋帅¹^,⁴^,*()

1. 安徽医科大学药学科学学院，合肥 230032，安徽
2. 安庆市立医院药事管理科，安庆 246003，安徽
3. 安徽贝克生物制药有限公司，合肥 230088，安徽
4. 安徽医科大学第一附属医院药剂科，合肥 230022，安徽

收稿日期:2025-03-11 修回日期:2025-06-14 出版日期:2026-07-26 发布日期:2026-08-04
通讯作者: 宋帅 E-mail:18609660653@163.com;songshuai@ahmu.edu.cn
作者简介:李林，男，主管药师，研究方向：临床药理学。E-mail：18609660653@163.com
基金资助:
安徽省转化医学研究院科研项目（2021zhyx-C37）；安徽省高校科研项目（2022AH051154）；安徽省“十三五”临床重点专科建设项目（卫科教秘[2017]529号）

Bioequivalence study of levodopa and benserazide hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions

Lin LI¹^,²(), Yuming XIA³, Chenlin SHEN¹, Quan XIA¹^,⁴, Shuai SONG¹^,⁴^,*()

1. School of Pharmaceutical Sciences, Anhui Medical University, Hefei 230032, Anhui, China
2. Department of Pharmaceutical Administration, Anqing Municipal Hospital, Anqing 246003, Anhui, China
3. Anhui Biochem Bio-Pharmceutical Corporation Limited, Hefei 230088, Anhui, China
4. Department of pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, China

Received:2025-03-11 Revised:2025-06-14 Online:2026-07-26 Published:2026-08-04
Contact: Shuai SONG E-mail:18609660653@163.com;songshuai@ahmu.edu.cn

摘要/Abstract

摘要：

目的: 评价空腹和餐后给药条件下，健康受试者口服两种多巴丝肼片的生物等效性。方法: 采用随机、开放、单剂量、两序列、四周期、完全重复交叉试验设计。纳入64例健康受试者，空腹和餐后均入组32例受试者，各分为两组，每组16例。每周期服用受试制剂1片或参比制剂1片，5天后交叉给药，清洗期均为 5 d。采用液相色谱串联质谱法测定左旋多巴和三羟基苄肼的血药浓度，使用 WinNonlin 8.1软件计算其药动学参数，评价两制剂的生物等效性。结果: 空腹给药后，受试制剂和参比制剂的左旋多巴C_max分别为（4261.10±1709.86）和（4157.00±1538.07）ng/mL，AUC_0-t分别为（7427.57±1409.34）和（7060.07±1389.62）h·ng·mL^?1、AUC_0-∞分别为（7472.97±1411.51）和（7146.98±1295.45）h·ng·mL^?1；三羟基苄肼C_max分别为（27.99±13.38）和（26.56±14.06）ng/mL、AUC_0-t分别为（17.85±6.00）和（17.22±5.39）h·ng·mL^?1、AUC_0-∞分别为（19.00±6.39）和（18.39±5.85）h·ng·mL^?1。餐后试验中，受试制剂和参比制剂的左旋多巴C_max分别为（3338.28±1493.52）和（3325.30±1524.62）ng/mL、AUC_0-t分别为（6744.79±1325.04）和（6615.38±1364.12）h·ng·mL^?1、AUC_0-∞分别为（6786.27±1326.03）和（6658.58±1358.30）h·ng·mL^?1；三羟基苄肼C_max分别为（8.35±6.49）和（8.44±6.44）ng/mL、AUC_0-t分别为（6.71±4.14）和（6.81±3.79）h·ng·mL^?1、AUC_0-∞分别为（7.14±4.27）和（7.23±3.98）h·ng·mL^?1。空腹和餐后试验中受试和参比制剂主要药动学参数的几何均值比90%CI均在80.00%～125.00%。试验期共发生27例次（空腹17例次，餐后10例次）不良事件，无严重不良事件。结论: 空腹和餐后给药条件下，受试者口服受试制剂与参比制剂具备生物等效性，且二者安全性良好。

关键词: 多巴丝肼, 生物等效性, 左旋多巴, 三羟基苄肼

Abstract:

AIM: To evaluate the bioequivalence of generic and original levodopa-benserazide tablets in healthy Chinese subjects under fasting and fed conditions. METHODS: A randomized, open-label, single-dose, two-sequence, four-period, fully replicated crossover study design was employed. A total of 64 healthy subjects were enrolled, with 32 subjects in the fasting group and 32 in the fed group, each divided into two groups of 16 subjects. Each subject received either one tablet of the test formulation or one tablet of the reference formulation in each period, with a washout period of 5 days between doses. The plasma concentrations of levodopa and tri-hydroxybenzylhydrazine were measured using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated using WinNonlin 8.1 software to assess the bioequivalence of the two formulations. RESULTS: Under fasting conditions, the C_max of levodopa for the test and reference formulations were (4261.10±1709.86) ng/mL and (4157.00±1538.07) ng/mL, respectively. The AUC_0-t values were (7427.57±1409.34) h·ng·mL^?1 and (7060.07±1389.62) h·ng·mL^?1, while AUC_0-∞ values were (7472.97±1411.51) h·ng·mL^?1 and (7146.98±1295.45) h·ng·mL^?1, respectively. For tri-hydroxybenzylhydrazine, C_max values were (27.99±13.38) ng/mL and (26.56±14.06) ng/mL; AUC_0-t were (17.85±6.00) h·ng·mL^?1 and (17.22±5.39) h·ng·mL^?1, respectively; and AUC_0-∞values were (19.00±6.39) h·ng·mL^?1 and (18.39±5.85) h·ng·mL^?1, respectively. In the fed trials, the C_max of levodopa for the test and reference formulations were (3338.28±1493.52) ng/mL and (3325.30±1524.62) ng/mL, respectively; AUC_0-t values were (6744.79±1325.04) h·ng·mL^?1 and (6615.38±1364.12) h·ng·mL^?1, respectively; and AUC_0-∞ values were (6786.27±1326.03) h·ng·mL^?1 and (6658.58±1358.30) h·ng·mL^?1, respectively. The C_max, AUC_0-t, and AUC_0-∞ values for trihydroxybenzylhydrazine were (8.35 ± 6.49) and (8.44 ± 6.44) ng/mL, (6.71 ± 4.14) and (6.81 ± 3.79) h·ng·mL^?1, and (7.14 ± 4.27) and (7.23 ± 3.98) h·ng·mL^?1, respectively.The geometric mean ratios of the primary pharmacokinetic parameters for both formulations under fasting and fed conditions fell within the 90% confidence interval of 80.00%-125.00%. A total of 27 adverse events were reported during the study (17 in the fasting group and 10 in the fed group), with no serious adverse events occurring. CONCLUSION: The test formulation demonstrates bioequivalence to the reference formulation in healthy subjects under both fasting and fed conditions, with a favorable safety profile.

Key words: benserazide, bioequivalence, levodopa, tri-hydroxybenzylhydrazine

中图分类号:

R969

李林, 夏玉明, 沈陈林, 夏泉, 宋帅. 多巴丝肼片在中国健康受试者中空腹和餐后条件下的生物等效性研究[J]. 中国临床药理学与治疗学, 2026, 31(7): 899-907.

Lin LI, Yuming XIA, Chenlin SHEN, Quan XIA, Shuai SONG. Bioequivalence study of levodopa and benserazide hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(7): 899-907.

图/表 8

表 1

Table 1 Demographic data of enrolled healthy subjects

Group	Age (year)	Weight (kg)	Height (cm)	BMI (kg/m²)
Fasting	31.44±5.29^a	67.03±6.97^a	171.4±5.52^a	22.81±1.86^a
Fasting	31.00±3.69^b	65.33±8.55^b	168.5±7.07^b	22.93±1.78^b
Fed	30.81±4.82^a	67.66±8.20^a	171.9±7.71^a	22.87±2.22^a
Fed	30.13±4.75^b	69.39±8.52^b	172.1±8.03^b	23.38±1.87^b

图 1

Fig.1 Representative chromatograms of levodopa in blank plasma and plasma at lower limit of quantification A: blank plasma sample; B: minimum quantitative lower limit plasma sample;IS: internal standard.

图 2

Fig.2 Representative chromatogram of levodopa in plasma from healthy subjects IS: iInternal standard.

图 3

Fig.3 Representative chromatogram of TRH in plasma from healthy subjects A: blank plasma sample; B: minimum quantitative lower limit plasma sample; C: subject plasma sample.

图 4

Fig.4 Mean plasma concentration-time curves of levodopa in healthy subjects under fasting (A) and fed (B) conditions after oral administration of the reference formulation (R) and the test formulation (T) of levodopa and benserazide hydrochloride tablets

图 5

Fig.5 Mean plasma concentration-time curves of TRH (Tri-hydroxybenzylhydrazine) in healthy subjects under fasting (A) and fed (B) conditions after oral administration of the reference formulation (R) and the test formulation (T) of levodopa and benserazide hydrochloride tablets.

表 2

Table 2 Main pharmacokinetic parameters of levodopa in healthy subjects under fasting and fed conditions

Parameter	Fasting		Fed
Parameter	Test (n=32)	Reference (n=32)	Test (n=31)	Reference (n=31)
T_max (h)	0.74 (0.33, 3.99)	0.74 (0.33, 3.99)	1.24 (0.50, 4.99)	1.24 (0.49, 4.99)
C_max (ng/mL)	4261.10± 1709.86	4157.00 ± 1538.07	3338.28± 1493.52	3325.30 ± 1524.62
AUC_0-t (h·ng·mL^?1)	7427.57 ± 1409.34	7060.07 ± 1389.62	6744.79± 1325.04	6615.38 ± 1364.12
AUC_0-∞ (h·ng·mL^?1)	7472.97 ± 1411.51	7146.98 ± 1295.45	6786.27 ± 1326.03	6658.58± 1358.30
λ_z (h^?1)	0.37 ± 0.09	0.42 ± 0.11	0.42 ± 0.11	0.41 ± 0.11
t_1/2 (h)	2.06 ± 1.27	1.76 ± 0.48	1.80 ± 0.64	1.82 ± 0.65

表 3

Table 3 Main pharmacokinetic parameters of Tri-hydroxybenzylhydrazine in healthy subjects under fasting and fed conditions

Parameter	Fasting		Fed
Parameter	Test (n=32)	Reference (n=32)	Test (n=31)	Reference (n=31)
T_max (h)	0.49 (0.16, 1.49)	0.49 (0.16, 1.49)	0.99 (0.33, 3.99)	0.75 (0.33, 2.25)
C_max (ng/mL)	27.99 ± 13.38	26.56 ± 14.06	8.35 ± 6.49	8.44 ± 6.44
AUC_0-t (h·ng·mL^?1)	17.85 ± 6.00	17.22 ± 5.39	6.71 ± 4.14	6.81 ± 3.79
AUC_0-∞ (h·ng·mL^?1)	19.00 ± 6.39	18.39 ± 5.85	7.14 ± 4.27	7.23 ± 3.98
λ_z (h^?1)	0.15 ± 0.07	0.17 ± 0.15	0.45 ± 0.24	0.39 ± 0.17
t_1/2 (h)	5.76 ± 3.56	6.06 ± 4.26	2.03 ± 1.23	2.42 ± 1.81

参考文献 17

1	Hauser RA. Levodopa: past, present, and future[J]. Eur Neurol, 2009, 62 (1): 1- 8. doi: 10.1159/000215875
2	Frank C, Chiu R, Lee J. Parkinson disease primer, part 1: diagnosis[J]. Can Fam Physician, 2023, 69 (1): 20- 24. doi: 10.46747/cfp.690120
3	Haddad F, Sawalha M, Khawaja Y, et al. Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease[J]. Molecules, 2017, 23 (1): 40. doi: 10.3390/molecules23010040
4	Salat D, Tolosa E. Levodopa in the treatment of Parkinson's disease: current status and new developments[J]. J Parkinsons Dis, 2013, 3 (3): 255- 269. doi: 10.3233/jpd-130186
5	高变异药物生物等效性研究技术指导原则 [EB/OL]. (2018-10-29). https://www.cde.org.cn/zdyz/domesticinfopagezdyzIdCODE=333fd2eac0928e881578082373233f8a.
6	Haidar SH, Davit B, Chen ML, et al. Bioequivalence approaches for highly variable drugs and drug products[J]. Pharm Res, 2008, 25 (1): 237- 241. doi: 10.1007/s11095-007-9434-x
7	Baruzzi A, Contin M, Riva R, et al. Influence of meal ingestion time on pharmacokinetics of orally administered levodopa in parkinsonian patients[J]. Clin Neuropharmacol, 1987, 10 (6): 527- 537. doi: 10.1097/00002826-198712000-00004
8	Contin M, Riva R, Martinelli P, et al. Effect of meal timing on the kinetic dynamic profile of levodopa/carbidopa controlled release in parkinsonian patients[J]. Eur J Clin Pharmacol, 1998, 54 (4): 303- 308. doi: 10.1007/s002280050464
9	Agnieszka W, Paweł P, Małgorzata K. How to Optimize the Effectiveness and Safety of Parkinson's Disease Therapy? - A Systematic Review of Drugs Interactions with Food and Dietary Supplements[J]. Curr Neuropharmacol, 2022, 20 (7): 1427- 1447.
10	Tsui JK, Ross S, Poulin K, et al. The effect of dietary protein on the efficacy of L-dopa: a double-blind study[J]. Neurology, 1989, 39 (4): 549- 552.
11	Carter JH, Nutt JG, Woodward WR, et al. Amount and distribution of dietary protein affects clinical response to levodopa in Parkinson's disease[J]. Neurology, 1989, 39 (4): 552- 556. doi: 10.1212/wnl.39.4.552
12	Robertson DR, Higginson I, Macklin BS, et al. The influence of protein containing meals on the pharmacokinetics of levodopa in healthy volunteers[J]. Br J Clin Pharmacol, 1991, 31 (4): 413- 417. doi: 10.1111/j.1365-2125.1991.tb05555.x
13	Leenders KL, Poewe WH, Palmer AJ, et al. Inhibition of L-[18F] fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography[J]. Ann Neurol, 1986, 20 (2): 258- 262. doi: 10.1002/ana.410200212
14	Crevoisier C, Zerr P, Calvi-Gries F, et al. Effects of food on the pharmacokinetics of levodopa in a dual-release formulation[J]. Eur J Pharm Biopharm, 2003, 55 (1): 71- 76. doi: 10.1016/s0939-6411(02)00124-8
15	Linazasoro G, Gorospe A. Treatment of complicated Parkinson disease with a solution of levodopa-carbidopa and ascorbic acid[J]. Neurologia, 1995, 10 (6): 220- 223.
16	Nagayama H, Hamamoto M, Ueda M, et al. The effect of ascorbic acid on the pharmacokinetics of levodopa in elderly patients with Parkinson disease[J]. Clin Neuropharmacol, 2004, 27 (6): 270- 273. doi: 10.1097/01.wnf.0000150865.21759.bc
17	Montioli R, Voltattorni CB, Bertoldi M. Parkinson's Disease: Recent Updates in the Identification of Human Dopa Decarboxylase Inhibitors[J]. Curr Drug Metab, 2016, 17 (5): 513- 518. doi: 10.2174/138920021705160324170558

[1]	谢晶, 王小妮, 闵捷, 刘敏, 朱旭, 胡旺, 卢畅, 张冉, 周焕, 宫建. 盐酸达拉他韦片在中国健康受试者中的生物等效性研究[J]. 中国临床药理学与治疗学, 2026, 31(1): 55-62.
[2]	王琰, 夏玉明, 朱仁弟, 欧阳紫微, 程远志, 周仁鹏, 胡伟. 利托那韦片在中国健康受试者中的生物等效性试验[J]. 中国临床药理学与治疗学, 2025, 30(9): 1193-1199.
[3]	陈璐, 李晓斌, 马雯霞, 谢红瑜, 王文萍. 利伐沙班片在中国健康受试者体内的生物等效性研究[J]. 中国临床药理学与治疗学, 2025, 30(6): 789-795.
[4]	王建雄, 胡晓, 苗贝贝, 张兰. PBPK模型及其在生物等效性研究中的应用进展[J]. 中国临床药理学与治疗学, 2025, 30(2): 244-250.
[5]	解染, 程璐, 周双, 张雪媛, 王晓如, 赵侠, 何旭, 赵楠, 贾博, 崔一民. 利伐沙班片在中国健康受试者中的药动学及生物等效性评价[J]. 中国临床药理学与治疗学, 2024, 29(11): 1295-1299.
[6]	燕强勇, 向大雄, 朱荣华, 杨玲凤, 阳喜定, 李晶晶, 范晓, 刘赛, 熊守军, 方平飞. 盐酸西那卡塞片在中国健康人群的生物等效性研究[J]. 中国临床药理学与治疗学, 2023, 28(2): 171-177.
[7]	肖雷, 徐媛媛, 黄晓青, 张文, 曹阳, 谢晶, 周焕, 黄顺旺. 醋酸地塞米松片在中国健康受试者中的生物等效性研究[J]. 中国临床药理学与治疗学, 2023, 28(12): 1365-1371.
[8]	李雪静, 江金平, 李思凝, 万林飞, 周响响, 杨梿, 兰轲. 一项在中国精神分裂症受试者中评估氯氮平片的生物等效性研究[J]. 中国临床药理学与治疗学, 2023, 28(10): 1121-1130.
[9]	刘敏, 孔祥, 章叶, 顾逸飞, 项雪梅, 黄凯. 经口吸入制剂在中国健康受试者生物等效性试验中的安全性分析[J]. 中国临床药理学与治疗学, 2023, 28(10): 1131-1138.
[10]	顾逸飞, 储楠楠, 黄凯, 阙琳玲, 张继胜, 项雪梅, 贺晴. 药效动力学研究在经口吸入制剂生物等效性评价中的应用进展[J]. 中国临床药理学与治疗学, 2022, 27(7): 822-833.
[11]	吴娟, 王志强, 周仁鹏, 杨晶晶, 秦慧玲, 张茜, 鲁超, 胡伟. 甲苯磺酸索拉非尼片在中国健康受试者的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(3): 281-286.
[12]	史革鑫, 崇锐, 贺坤, 吴海棠, 周宇, 顿中军, 温清, 张继国, 张荣. 吗替麦考酚酯胶囊在中国健康男性受试者空腹及餐后状态下的完全重复交叉设计的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(11): 1255-1263.
[13]	胡殷, 杨丹丹, 徐毅超, 邵蓉, 阮邹荣, 江波, 陈金亮, 楼洪刚. 人工神经网络模型在坎地沙坦酯片生物等效性研究中的应用[J]. 中国临床药理学与治疗学, 2022, 27(1): 63-69.
[14]	蔡名敏, 邵静, 唐璐, 孙秋月, 窦婷, 钱薇, 王慧萍. 丁苯酞注射液在中国健康人体内的生物等效性研究[J]. 中国临床药理学与治疗学, 2022, 27(1): 70-76.
[15]	郑斌婕, 刘娜, 曾祥昌, 黄馨仪, 陈露露, 欧阳冬生. 肠道菌群对药物代谢动力学的影响及其在仿制药质量与疗效一致性评价中的思考[J]. 中国临床药理学与治疗学, 2021, 26(6): 662-671.

多巴丝肼片在中国健康受试者中空腹和餐后条件下的生物等效性研究

Bioequivalence study of levodopa and benserazide hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 8

参考文献 17

相关文章 15

编辑推荐

Metrics

本文评价