Koopman Sjoerd F, Cnossen Marjon H, Mathot Ron A A
Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Clin Pharmacol Ther. 2025 Oct;118(4):831-840. doi: 10.1002/cpt.3724. Epub 2025 May 19.
In hemophilia B, pharmacokinetic (PK)-guided dosing of extended half-life factor IX (EHL-FIX) concentrates can secure targeted FIX exposure. Target FIX activity levels in plasma should be individually set primarily taking bleeding tendency into account, alongside the presence of target joints, physical activity, and preferred dosing schedules. In other words, both PK and pharmacodynamics (PD) are relevant when individualizing therapy. Our objective was to examine the relationship between dose, FIX activity levels, and bleeding specifically for EHL-FIX concentrate recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP). Data from hemophilia B patients with endogenous FIX activity level ≤ 2 IU/dL from five clinical trials were combined. Bleeding probability was described with a parametric repeated time-to-event (RTTE) model. Data included 2,493 FIX activity levels and 514 bleeds from 114 unique patients with a median age of 26 years (range: 1-61) followed for a median of 416 days (range: 6-1,233). Joints were the most frequent bleeding site (46%), and more than half of the bleeds were trauma-related (52%). Overall, 60% and 40% were categorized as damage-causing or nuisance bleeds, respectively. A baseline hazard of 7.3 bleeds per year was calculated when FIX activity levels were set at zero. The probability of all bleeding decreased by 50% when the FIX activity level was 12 IU/dL. Variability in bleeding hazard between individuals with similar FIX activity levels was substantial (182%). Simulations showed that targeting trough FIX activity levels to 20 IU/dL resulted in a median annual bleeding rate (ABR) of zero (range: 0-3).
在乙型血友病中，延长半衰期的凝血因子IX（EHL-FIX）浓缩物的药代动力学（PK）指导给药可确保达到目标FIX暴露水平。血浆中的目标FIX活性水平应主要根据出血倾向来个体化设定，同时考虑目标关节的存在、身体活动情况以及首选的给药方案。换句话说，在个体化治疗时，PK和药效学（PD）都很重要。我们的目的是专门研究剂量、FIX活性水平与出血之间的关系，具体针对将凝血因子IX与白蛋白连接的重组融合蛋白EHL-FIX浓缩物（rIX-FP）。合并了来自五项临床试验的内源性FIX活性水平≤2IU/dL的乙型血友病患者的数据。用参数化重复事件发生时间（RTTE）模型描述出血概率。数据包括来自114例独特患者的2493个FIX活性水平和514次出血事件，患者中位年龄为26岁（范围：1 - 61岁），中位随访时间为416天（范围：6 - 1233天）。关节是最常见的出血部位（46%），超过一半的出血与创伤有关（52%）。总体而言，分别有60%和40%的出血被归类为致伤性出血或轻微出血。当FIX活性水平设定为零时，计算出每年的基线出血风险为7.3次。当FIX活性水平为12IU/dL时，所有出血的概率降低了50%。FIX活性水平相似的个体之间出血风险的变异性很大（182%）。模拟结果表明，将谷值FIX活性水平目标设定为20IU/dL时，中位年出血率（ABR）为零（范围：0 - 3）。
