奥贝胆酸在肝损害患者的剂量选择及FDA定量审评的考虑  

Dose selection of obeticholic acid in hepatic impairment patients and the review consideration of FDA

作　　者：高丽丽 陈蕊 李禄金[1] 郑青山[1] GAO Lili;CHEN Rui;LI Lujin;ZHENG Qingshan(Center for Drug Clinical Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海中医药大学药物临床研究中心,上海201203

出　　处：《中国临床药理学与治疗学》2021年第7期760-767,共8页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：科技创新行动计划(17401970900)。

摘　　要：奥贝胆酸(商品名为OCALIVA^(■))治疗原发性胆汁性肝硬化(PBC)的临床试验显示其疗效确切。由于在中重度肝损害人群中难以开展充分的临床研究,申请人与FDA定量药理学审评团队基于群体药动学模型、暴露-效应模型和生理药动学模型(PBPK)等研究报告不同解读,在剂量选择上意见不一。申请人认为,该药在肝脏组织中的暴露量增加有限,无需进行剂量调整,即5 mg,每日1次。FDA则认为,PBPK模型中该药的影响因素没有被充分考虑,外部验证数据有限且偏差较大,患者血药暴露过高同样存在风险,建议大幅下调剂量,即5 mg,每周1次,每周最大不超过10 mg,至少间隔3 d等滴定给药方案,并据此写入了用药说明书。上市后发生多例肝损害患者,均未按说明书提示,超量用药,导致死亡。结果充分证明,FDA当初的考虑和决策获得验证,而该药的经验和教训再次提示,建模与模拟需要大胆假设,小心求证。The clinical trial of OBCA(OCALIVA^(■))in the treatment of primary biliary cirrhosis(PBC)shows its efficacy.As it is difficult to conduct sufficient clinical studies in moderate and severe hepatic impairment population,the applicant and the FDA theorem have different opinions based on the same model,such as population PK,exposure-response and physiologically-based PK(PBPK).The applicant considers that the increase in the exposure of drug in liver tissue is limited,and there is no need for dose adjustment,that is,5 mg,once a day.FDA believes that the influencing factors of the PBPK model have not been fully taken into account and the validation of the PBPK is not robust with a wide variability,and there is also a risk of high blood drug exposure in patients.It is recommended to significantly reduce the dose,that is,5 mg,once a week,no more than 10 mg,per week at least 3 days interval,and accordingly written into the medication instructions.After approval many patients with hepatic impairment did not take medicine according to the instructions,therefore overdosed,resulting in death.The results fully prove that the original considerations and decisions of FDA have been verified,and the experience and lessons of this example once again suggest that modeling and simulation need bold assumptions and careful verification.

关 键 词：模型引导的药物研发 特殊人群 暴露-效应关系 定量药理学 

分 类 号：R969[医药卫生—药理学]