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  

A bioequivalence study of generic and brand clozapine in schizophrenic patients

作　　者：李雪静 江金平 李思凝 万林飞 周响响 杨梿 兰轲 LI Xuejing;JIANG Jinping;LI Sining;WAN Linfei;ZHOU Xiangxiang;YANG Lian;LAN Ke(Chengdu Cynogen Bio-pharmaceutical Tech.Co,Chengdu 610000,Sichuan,China;Chengdu Health-Balance Medical Tech Co,Ltd,Chengdu 610000,Sichuan,China;West China School of Pharmacy,Sichuan University,Chengdu 610041,Sichuan,China)

机构地区：[1]成都赛璟生物医药科技有限公司,四川成都610095 [2]成都衡康医药科技有限公司,四川成都610095 [3]四川大学华西药学院,四川成都610041

出　　处：《中国临床药理学与治疗学》2023年第10期1121-1130,共10页Chinese Journal of Clinical Pharmacology and Therapeutics

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5~2000 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:T_(max,ss)分别为1.01~5.02 h和1.00~5.00 h;C_(max,ss)分别为(665.0±279.3)、(679.5±240.3)ng/mL;AUC_(0-τ)分别为(5408.1±2918.2)、(5389.5±2223.6)ng∙h∙mL^(-1);受试制剂和参比制剂药动学参数C_(max,ss)、AUC_(0-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。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,twoperiod,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 5-2000 ng/mL.The main pharmacokinetic parameters of test and reference formulation in plasma were shown as follows:T_(max,ss) were(1.01-5.02)and(1.00-5.00)h;C_(max,ss) were(665.0±279.3)and(679.5±240.3)ng/mL;AUC_(0-τ)were(5408.1±2918.2)and(5389.5±2223.6)ng∙h∙mL^(-1),respectively.The 90%confidence intervals(CIs)for the natural logarithmically transformed C_(max,ss) and AUC_(0-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.

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 

分 类 号：R969.1[医药卫生—药理学] R971.4[医药卫生—药学]