During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. Maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and bleed information from patient diaries. Each patients' time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and bleed number (from patient diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (N=187; 815 patient-years' exposure), factor VIII activity was predicted to reach >1% for 85.64% of the time. Annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase, and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. Target trough and prophylactic regimen should consider patient age, joint disease activity, and other bleeding risk determinants.

译文

:在预防严重的A型血友病的VIII因子治疗期间,当VIII因子活性低于1%时出血风险随时间增加。维持食槽活动高于1%并不能保护所有患者免于流血。预防期间VIII因子活性与出血风险之间的关系尚未得到彻底研究。我们调查了预防期间自发性出血的凝血因子VIII活性和年度出血率。将源自三项临床试验的总体药代动力学模型与剂量数据和患者日记中的出血信息相结合。将每个患者的预防时间分为五类预测活动(0-1%,> 1-5%,> 5-15%,> 15-50%和> 50%)。计算每种活动类别的暴露时间,平均VIII因子活性和出血数(来自患者日记),并使用负二项式回归和参数模型估算年化出血率。通过试验阶段(枢纽性与扩展性)和年龄(成人/青少年[≥12岁]对儿童[0- <12岁])评估了这些出血率与VIII因子活性之间的关系。总计(N = 187; 815患者-年的暴露量),因子VIII的活性预计将在85.64%的时间内达到> 1%。在每个试验阶段和年龄组中,随着因子VIII活性的增加,年度出血率降低。但是,对于给定的活动水平,出血率因试验阶段和年龄而有很大差异。这表明出血风险可以随时间变化,并且受与因子VIII药代动力学和谷值水平无关的因素影响。目标槽和预防方案应考虑患者年龄,关节疾病活动和其他出血风险决定因素。

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