Huang Kun, Wang Yan, Zhen Yingzi, Li Gang, Wu Xinyi, Zhang Ningning, Chen Zhenping, Wu Runhui
Hematology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045; Hematologic Disease Laboratory, Hematology Center, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, China, 100045.
Rehabilitation Department, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 100045, China.
Thromb Res. 2022 May;213:71-77. doi: 10.1016/j.thromres.2022.03.008. Epub 2022 Mar 12.
As the most commonly used FVIII concentrate in China, the individualized pharmacokinetics (PK) and clinical outcomes of Kovaltry (BAY81-8973) are not fully investigated in this population.
Pediatric patients with severe hemophilia A were enrolled in Beijing Children's Hospital. After a three-day washout, they received PK tests after a single-dose infusion of 50 IU/kg. The blood samples were collected with a six-point assay. One-stage-based activated partial thromboplastin time was used for FVIII activity. The PK parameters were generated by WinNonlin software. The bleeding rates were calculated by their routine therapy record. The ultrasound was used to evaluate their both sides of knees, elbows and ankles.
Sixty-one boys with severe hemophilia A were enrolled and their median age was 5.73 years. Twenty-nine of them were blood group-O. Compared with blood group-O patients, those non-O patients showed longer t (15.26 vs. 13.03 h, P < 0.001) and reduced CL (3.04 vs. 3.66 mL/kg/h, P < 0.05). Patients with higher VWF:Ag level had longer half-life time (t) (r = 0.60, P < 0.0001) and lower clearance (CL) (r = -0.45, P < 0.001). Patients with higher trough level showed decreased bleeding rates compared with those owning a trough level below 1 IU/dL (P < 0.05). In general, the zero bleeding rates raised with elevation of trough level. However, 20-30% of patients with low trough level (<1 IU/dL) also showed no bleeds and 10-20% of patients with high trough level (>5 IU/dL) still suffer bleeds. An inconsistency of 28% between joint bleeds and ultrasound evaluation was showed.
This study revealed the great inter-individual variability in PK parameters, clinical bleeding phenotype and joint vulnerability, which all should be considered in treating hemophilia A.
作为中国最常用的FVIII浓缩物，科法曲（BAY81-8973）在该人群中的个体药代动力学（PK）和临床结局尚未得到充分研究。
在北京儿童医院招募患有重度A型血友病的儿科患者。经过三天的洗脱期后，他们接受单剂量50IU/kg输注后的PK测试。采用六点法采集血样。基于一期法的活化部分凝血活酶时间用于检测FVIII活性。PK参数由WinNonlin软件生成。根据他们的常规治疗记录计算出血率。使用超声评估他们双侧的膝盖、肘部和脚踝。
招募了61名患有重度A型血友病的男孩，他们的中位年龄为5.73岁。其中29人为O型血。与O型血患者相比，非O型血患者的t更长（15.26对13.03小时，P<0.001），清除率（CL）更低（3.04对3.66mL/kg/h，P<0.05）。血管性血友病因子抗原（VWF:Ag）水平较高的患者半衰期（t）更长（r=0.60，P<0.0001），清除率（CL）更低（r=-0.45，P<0.001）。谷值水平较高的患者与谷值水平低于≤1IU/dL的患者相比，出血率降低（P<0.05）。总体而言，零出血率随谷值水平升高而增加。然而，20%-30%谷值水平低（<1IU/dL）的患者也未出现出血，10%-20%谷值水平高（>5IU/dL）的患者仍有出血。关节出血与超声评估之间存在28%的不一致。
本研究揭示了PK参数、临床出血表型和关节易损性存在很大的个体间差异，在治疗A型血友病时均应予以考虑。
