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药物代谢动力学指导血友病A治疗的中国专家共识

中国血友病协作组

中国血友病协作组. 药物代谢动力学指导血友病A治疗的中国专家共识[J]. 罕见病研究, 2022, 1(4): 428-434. doi: 10.12376/j.issn.2097-0501.2022.04.011
引用本文: 中国血友病协作组. 药物代谢动力学指导血友病A治疗的中国专家共识[J]. 罕见病研究, 2022, 1(4): 428-434. doi: 10.12376/j.issn.2097-0501.2022.04.011
Hemophilia Treatment Center Collaborative Network of China. Chinese Expert Consensus on Pharmacokinetics Guided Treatment for Hemophilia A[J]. Journal of Rare Diseases, 2022, 1(4): 428-434. doi: 10.12376/j.issn.2097-0501.2022.04.011
Citation: Hemophilia Treatment Center Collaborative Network of China. Chinese Expert Consensus on Pharmacokinetics Guided Treatment for Hemophilia A[J]. Journal of Rare Diseases, 2022, 1(4): 428-434. doi: 10.12376/j.issn.2097-0501.2022.04.011

药物代谢动力学指导血友病A治疗的中国专家共识

doi: 10.12376/j.issn.2097-0501.2022.04.011
基金项目: 

“十三五”国家重点研发计划精准医学研究重点专项 2016YFC0901503

中国医学科学院医学与健康科技创新工程重大协同创新项目 2017-I2M-3-018

中国医学科学院医学与健康科技创新工程重大协同创新项目 2016-I2M-1-002

杨仁池, E-mail: rcyang65@163.com
执笔: 陈振萍,刘葳,蔡力生
详细信息
  • 中图分类号: R554+.1

Chinese Expert Consensus on Pharmacokinetics Guided Treatment for Hemophilia A

Funding: 

National Key Research and Development Program of China 2016YFC0901503

CAMS Innovation Fund for Medical Sciences 2017-I2M-3-018

CAMS Innovation Fund for Medical Sciences 2016-I2M-1-002

YANG Renchi, E-mail: rcyang65@163.com
Writers: CHEN Zhenping, LIU Wei, CAI Lisheng
  • 摘要: 血友病A是一种以凝血因子Ⅷ(FⅧ)缺乏,临床表现为自发性或者损伤后过度出血的X染色体连锁隐性遗传病。血友病A目前主要治疗方式是替代性输注FⅧ, 但对于输注的剂量、频次大多仍采用固定输注模式, 并不能达到个体化治疗原则下的最优疗效。影响FⅧ替代治疗疗效的因素中, 个体对FⅧ产品的药物代谢动力学(PK)差异是一个重要因素。临床对于PK指导下的个体化FⅧ替代治疗认知尚不充分, 因此本文就FⅧ的PK特征、分析模型、临床应用场景与具体治疗方案制定进行分析,并为临床实践提供指导意见。

     

  • 图  1  主要的PK参数

    FⅧ ∶C为凝血因子Ⅷ活性; T(h)为时间(小时); Baseline为基线水平; Cmax为峰浓度; Ctrough为谷浓度; CL为清除率; D为剂量; AUC为曲线下面积; t1/2为半衰期; ln为自然对数函数; Ke为消除速率常数

    Figure  1.  Major PK parameters

    表  1  不同PK分析方法比较

    Table  1.   Comparison of the different PK aralysis methods

    经典的个体PK分析 基于popPK和贝叶斯算法的个体PK分析 基于经典PK改良的一室模型分析
    myPKFiT WAPPS-HEMO
    洗脱期 72 h
    采样时间点 成人11个, 儿童5~6个[25] 2~3个 推荐3个, 至少1个 2个
    给药剂量 50 IU/kg 推荐10~100 IU/kg 无推荐, 可用常规预防剂量 无推荐, 可用常规预防剂量
    分析模型 多采用非房室模型 二室模型; 基于NONMEM软件拟合贝叶斯算法, 形成特有的Björkman模型[24] 二室模型; 基于NONMEM软件拟合贝叶斯预测[26] 一室模型[24]; 通过EXCEL计算程序
    PK软件 通用PK软件、未作为医疗器械获批 国家药品监督管理局获批的医疗器械(16岁以上) 科研性质的软件, 在中国未作为医疗器械获批 未作为医疗器械获批
    数据库 离线分析, 不涉及数据库 在线分析, 数据库在中国 在线分析, 数据库在加拿大 离线分析, 不涉及数据库
    适用FⅧ产品 已上市的FⅧ/FⅨ产品 ADVATEa 已上市的FⅧ/FⅨ产品 已上市的FⅧ产品
    建模数据 无需建模 ADVATE特有模型[27]b 多种FⅧ/FⅨ模型[23, 26]c 无需建模
    PK分析时效 实时 实时 约2~3 d[26] 实时
    PK模型的验证 不适用 稀疏采样数据验证模型; 进行了适用性和可信性检查; 使用不包括在构建群体PK模型中的临床研究数据进行了外部验证[17] 需进一步改进和验证所有模型[28]; 需使用稀疏采样数据验证模型[26]; 评估预测优度和可靠性需在前瞻性临床试验中评估 由于一室模型不能预测FⅧ分布相的代谢, 半衰期和峰浓度的预测会有偏差, 需进一步在前瞻性研究中验证
    输出信息 Cmax、CL、Vss、t1/2lamda、AUC、MRT等PK参数 CL、Vss、t1/2、FⅧ∶C大于1%的时间和剂量计算a; 基于以上结果可以根据临床需求设定目标谷浓度(例如5%)、给药间隔, 软件可因此计算提供相应治疗方案 t1/2、至5%、2%和1%活性的时间、输注后24、48和72 h的预期血浆水平[26]; 临床计算器可制定不同谷水平的治疗方案, 或对目标方案预测其谷水平 t1/2, 预测注射FⅧ 3 h之后的活性(预测第0~3 h活性比实际活性低);可设定目标水平和输注间隔计算预防治疗方案, 围手术期FⅧ使用量计算
    a参考myPKFiT用户手册第2.0.11版; b为myPKFIT建模使用2035样本, 152个体(ADVATE特有模型); 其中青少年和成人数据为1 829样本, 100个体(10~65岁); 儿童数据为206样本, 52个体(1~6岁); c为WAPPS-HEMO建模共使用878样本, 289个体(包含使用多种FⅧ/FⅨ的个体), 模型中无12岁以下儿童数据
    下载: 导出CSV
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  • 收稿日期:  2022-04-14
  • 录用日期:  2022-06-22
  • 网络出版日期:  2022-12-23

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