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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
doi: 10.12376/j.issn.2097-0501.2022.04.011
杨仁池, E-mail: rcyang65@163.com
执笔: 陈振萍，刘葳，蔡力生
执笔: 陈振萍，刘葳，蔡力生
Chinese Expert Consensus on Pharmacokinetics Guided Treatment for Hemophilia A
YANG Renchi, E-mail: rcyang65@163.com
Writers: CHEN Zhenping, LIU Wei, CAI Lisheng
Writers: CHEN Zhenping, LIU Wei, CAI Lisheng
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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。Abstract: Hemophilia A is an X-chromosome-linked recessive genetic disease that lacks coagulation factor Ⅷ (Factor Ⅷ, FⅧ) and is clinically manifested as spontaneous or excessive bleeding after injury.The current main treatment for hemophilia A is alternative infusion of FⅧ, but the fixed infusion mode is still used for the dosage and frequency of infusion, which cannot achieve the optimal curative effect under the principle of individualized treatment.Among the factors that affect the efficacy of FⅧ replacement therapy, the difference in the pharmacokinetics (PK) of FⅧ products by individuals is an important factor.The clinical understanding of individualized FⅧ replacement therapy under the guidance of PK is not sufficient.Therefore, this article reviews the PK characteristics, analysis models, clinical application scenarios and specific treatment plan formulation of FⅧ.
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Key words:
- hemophilia A /
- coagulation factor Ⅷ /
- pharmacokinetics /
- personalization
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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 无 无 无 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 
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