目前对FVIII药代动力学变异遗传修饰因子的认识。

IF 1.8 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pharmacogenomics & Personalized Medicine Pub Date : 2023-01-01 DOI:10.2147/PGPM.S383221
Laura L Swystun, David Lillicrap
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引用次数: 1

摘要

遗传性出血性疾病血友病A涉及凝血辅助因子VIII (FVIII)的定量缺乏。用FVIII浓缩液预防性治疗严重血友病A患者的目的是减少自发性关节出血的频率,并需要个性化定制给药方案,以考虑FVIII药代动力学的巨大个体间差异。FVIII药代动力学(PK)指标在同一个体的重复分析中具有很强的可重复性,表明该性状受遗传调控。虽然血浆血管性血友病因子抗原(VWF:Ag)水平、ABO血型和患者年龄对FVIII PK的影响已经得到了很好的证实,但估计表明,这些因素占FVIII PK总体变异性的比例不到35%。最近的研究已经确定了改变FVIII清除率或半衰期的遗传决定因素,包括VWF基因变异,这些变异会损害VWF-FVIII的结合,从而加速清除无VWF的FVIII。此外,调节FVIII清除或VWF-FVIII复合物的受体变异与FVIII PK有关。FVIII PK遗传修饰因子的表征将为具有临床意义的主题提供机制见解,并支持针对a型血友病患者制定个性化治疗计划。
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Current Understanding of Inherited Modifiers of FVIII Pharmacokinetic Variation.

The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.

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来源期刊
Pharmacogenomics & Personalized Medicine
Pharmacogenomics & Personalized Medicine Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
3.30
自引率
5.30%
发文量
110
审稿时长
16 weeks
期刊介绍: Pharmacogenomics and Personalized Medicine is an international, peer-reviewed, open-access journal characterizing the influence of genotype on pharmacology leading to the development of personalized treatment programs and individualized drug selection for improved safety, efficacy and sustainability. In particular, emphasis will be given to: Genomic and proteomic profiling Genetics and drug metabolism Targeted drug identification and discovery Optimizing drug selection & dosage based on patient''s genetic profile Drug related morbidity & mortality intervention Advanced disease screening and targeted therapeutic intervention Genetic based vaccine development Patient satisfaction and preference Health economic evaluations Practical and organizational issues in the development and implementation of personalized medicine programs.
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