Institut national de la santé et de la recherche médicale (Inserm), UMR 1059, Dysfonction Vasculaire et de l'Hémostase, Université de Lyon, Saint Etienne, France.
Unité d'Hémostase Clinique, Hôpital Cardiologique Louis Pradel, Université Lyon 1, Lyon, France.
Haemophilia. 2020 Mar;26(2):228-235. doi: 10.1111/hae.13935. Epub 2020 Feb 26.
For patients with severe haemophilia A, guidelines recommend prophylactic treatment with FVIII, with dose calculations targeting a predetermined FVIII trough level. However, this pharmacokinetic (PK) approach is suboptimal, with some patients experiencing breakthrough bleeds. We aimed to improve FVIII dosing by incorporating the thrombin generation assay, a global haemostasis assay whose main pharmacodynamic (PD) parameter, endogenous thrombin potential (ETP), predicts spontaneous bleeding risk.
We performed post hoc combined PK-PD modelling using data from 66 adults who received human-cl rhFVIII (Nuwiq , Octapharma AG) in a phase IIIb study. Time-to-event analyses simulated the probability of spontaneous bleeding for different FVIII exposures and baseline ETPs.
Ninety-one spontaneous bleeds occurred in 20/66 patients. The relationship between FVIII:C and ETP was non-linear, and the sigmoid Emax model adequately described the data. Individual PK-PD Bayesian estimation significantly improved predictive performance. Simulations showed that the mean spontaneous annual bleeding rate decreased with increasing baseline ETP or dosing: with ETP values of 200, 400 and 600 (nmol/L)·min annual bleeding rates were 2.36, 1.25 and 0.66, respectively, on 40 IU/kg human-cl rhFVIII every 3 days; and annual bleeding rates were 2.09, 1.10, and 0.60, respectively, on 60 IU/kg every 3 days.
Prophylactic FVIII dosing is more clinically meaningful when incorporating ETP alongside FVIII level. For the first time, FVIII dosing can be personalized with the aim of eliminating spontaneous breakthrough bleeds.
对于严重血友病 A 患者，指南建议使用 FVIII 进行预防性治疗，剂量计算针对预定的 FVIII 谷水平。然而，这种药代动力学（PK）方法并不理想，一些患者会出现突破性出血。我们旨在通过纳入血栓生成试验来改善 FVIII 剂量，该试验是一种全面的止血试验，其主要药效动力学（PD）参数，即内源性凝血酶潜能（ETP），可预测自发性出血风险。
我们使用在一项 IIIb 期研究中接受人源化 rhFVIII（诺维赛，Octapharma AG）的 66 名成年人的数据进行了事后 PK-PD 联合建模。时间事件分析模拟了不同 FVIII 暴露量和基线 ETP 下自发性出血的概率。
20/66 名患者中有 91 例自发性出血。FVIII:C 与 ETP 之间的关系是非线性的，Sigmoid Emax 模型很好地描述了数据。个体 PK-PD 贝叶斯估计显著提高了预测性能。模拟表明，随着基线 ETP 或剂量的增加，平均自发性年出血率降低：当 ETP 值分别为 200、400 和 600（nmol/L）·min 时，每 3 天给予 40 IU/kg 人源化 rhFVIII 的年出血率分别为 2.36、1.25 和 0.66；当每 3 天给予 60 IU/kg 时，年出血率分别为 2.09、1.10 和 0.60。
在结合 FVIII 水平的情况下，预防性 FVIII 剂量更具临床意义。首次可以通过个性化 FVIII 剂量来消除自发性突破性出血。
