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中国临床药理学与治疗学 ›› 2023, Vol. 28 ›› Issue (10): 1121-1130.doi: 10.12092/j.issn.1009-2501.2023.10.005

• 临床药理学 • 上一篇    下一篇

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

李雪静1，2，江金平1，李思凝1，万林飞1，周响响1，杨  梿1，2，兰  轲1，2，3   

  1. 1成都赛璟生物医药科技有限公司，成都  610095，四川；
    2成都衡康医药科技有限公司，成都  610095，四川；
    3四川大学华西药学院，成都  610041，四川
  • 收稿日期:2023-06-05 修回日期:2023-08-01 出版日期:2023-10-26 发布日期:2023-10-26
  • 作者简介:李雪静，女，硕士，中级工程师，研究方向：临床药学与生物样品分析。 E-mail: lixuejing@cynogen.com

A bioequivalence study of generic and brand clozapine in schizophrenic patients

LI Xuejing1,2, JIANG Jinping1, LI Sining1, WAN Linfei1, ZHOU Xiangxiang1, YANG Lian1,2, LAN Ke1,2,3   

  1. 1Chengdu Cynogen Bio-pharmaceutical Tech.Co, Chengdu 610000, Sichuan, China; 2Chengdu Health-Balance Medical Tech Co, Ltd, Chengdu 610000, Sichuan, China; 3West China School of Pharmacy, Sichuan University, Chengdu 610041, Sichuan, China
  • Received:2023-06-05 Revised:2023-08-01 Online:2023-10-26 Published:2023-10-26

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摘要： 目的：建立人血浆中氯氮平含量测定的UPLC-MS/MS分析方法评价国产和原研氯氮平片在中国精神分裂症患者体内的生物等效性和安全性。方法：采用两制剂、两周期、两序列交叉设计，24例受试者多剂量口服两种氯氮平片（每12 h口服100 mg），用UPLC-MS/MS方法测定其血药浓度，计算主要药动学参数，评价两种氯氮平片的生物等效性。结果：人血浆中氯氮平含量测定分析方法的线性范围为5～2 000 ng/mL，批内、批间精密度［RSD（%）］均小于5%。受试制剂与参比制剂的主要药动学参数：Tmax,ss分别为1.01～5.02 h和1.00～5.00 h；Cmax,ss分别为（665.0±279.3）、（679.5±240.3） ng/mL；AUC0-τ分别为（5 408.1±2 918.2）、（5 389.5±2 223.6）ng?h?mL-1；受试制剂和参比制剂药动学参数Cmax,ss、AUC0-τ几何均值比的90%置信区间分别落在86.15%～106.25%和87.69%～104.51%。结论：建立的分析方法灵敏、快速、准确，两种氯氮平片在受试者体内生物等效。

关键词: 氯氮平, 超高效液相色谱质谱联用法, 药动学, 稳态, 生物等效性

Abstract:

AIM: To establish a ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determination the plasma concentration of clozapine and compare the bioequivalence of a generic clozapine tablet with Clozaril?. METHODS: A randomized, open-label, multiple-dose, steady-state, two-treatment, two-period, crossover study was conducted on Schizophrenia patients who had been receiving a stable dose of clozapine for at least three months under fasting condition. Twenty-four schizophrenia patients were orally administrated with Clozaril tablets or the generic clozapine tablet 100 mg every 12 h for 10 days, then switched to the other formulation for the next 10 d. The concentrations of clozapine in plasma were determined by an estabilished UPLC-MS/MS method. RESULTS： The method was validated by investigating the accuracy and precision for intra and inter-day runs in a linear concentration from 5-2 000 ng/mL. The main pharmacokinetic parameters of test and reference formulation in plasma were shown as follows: Tmax,ss were (1.01-5.02) and (1.00-5.00) h；Cmax,ss were (665.0 ± 279.3) and (679.5 ± 240.3) ng/mL; AUC0-τ were 
(5 408.1 ± 2 918.2) and (5 389.5 ± 2 223.6) ng?h?mL-1, respectively. The 90% confidence intervals (CIs) for the natural logarithmically transformed Cmax,ss and AUC0-τ ratios were 86.15%-106.25% and 87.69%-104.51% under fasting condition. Safety/tolerability profiles were similar between formulations. CONCLUSION: The two tablet formulations are bioequivalent in Chinese subjects.

Key words: clozapine, UPLC-MS/MS, pharmacokinetics, steady-state, bioequivalence

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