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Abstract：
Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding.
摘要：
并非所有患有严重血友病A(HA)的患者对给定剂量的给定产品反应最佳。交叉研究中的个体内差异使每个患者在药代动力学（PK）术语中对每种标准半衰期（SHL）因子VIII（FVIII）产品的反应方面具有独特性。当使用SHLFVIII产品时,这妨碍了功效的预测。显示SHLrFVIII的半衰期不能令人满意地实现个体HA患者中的零出血的PK数据提供了从SHL转换到延长半衰期(EHL)产品的理由。然而,并非所有接受EHL产品预防的受试者均实现零出血，个性化预防的最有说服力的目标。FVIII半衰期的已知决定因素(年龄，vonWillebrand因子[VWF]水平，血型）累计占重度HA受试者FVIII清除率个体间总变异的三分之一。对精确度的调查，和实验室测量的准确性；清除游离FVIII和VWF结合的FVIII的新途径，以及对组学和表型异质性的充分动力研究，可能提供有关HA中FVIII清除的个体间差异的剩余三分之二的其他信息。当FVIII活性被固定皮下剂量的双特异性抗体emicizumab模拟时,临床反应的变异性也已在患者中得到证明。应鼓励收集现有FVIII产品的PK数据和个人对emicizumab反应的临时信息的国家注册管理机构，建立新的护理标准并简化个性化临床决策，以实现零出血。
