Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands.
Thromb Haemost. 2020 May;120(5):747-757. doi: 10.1055/s-0040-1709522. Epub 2020 May 5.
The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required.
Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM).
A total of 43 hemophilia A patients (FVIII ≤ 2 IU/dL), aged 5 to 70 years, were included. The prior model was able to predict the collected 244 rFVIII-Fc levels without significant bias (-1.0%, 95% CI: -9.4 to 7.3%) and with acceptable accuracy (12.9%). However, clearance and central distribution volume were under predicted in patients <12 years, which was expected as this age group was not represented in the previous model population. An enriched population PK model was constructed, which was able to successfully characterize PK profiles of younger children.
We concluded that the existing rFVIII-Fc population PK model is valid for patients ≥ 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients ≥5 years.
目前用于血友病患者 PK 指导剂量的已发表群体药代动力学（PK）模型是基于临床试验数据的，并且通常没有在临床实践中进行外部验证。本研究的目的是验证已发表的用于重组因子 VIII-Fc 融合蛋白（rFVIII-Fc）浓缩物的 PK 模型，并在需要时使用独立收集的临床数据开发一个丰富的模型。
收集参加英国延长半衰期结果登记处的接受 rFVIII-Fc 浓缩物（Elocta）治疗的血友病 A 患者的临床数据。使用均方百分比误差（偏差）和均方绝对百分比误差（不准确性）评估已发表模型的预测性能。使用非线性混合效应建模（NONMEM）开发扩展群体 PK 模型。
共纳入 43 名 FVIII≤2IU/dL 的血友病 A 患者（年龄 5 至 70 岁）。先前的模型能够预测采集的 244 个 rFVIII-Fc 水平，没有显著的偏差（-1.0%，95%CI：-9.4 至 7.3%），并且具有可接受的准确性（12.9%）。然而，在<12 岁的患者中，清除率和中央分布容积被低估，这是预期的，因为这个年龄组在之前的模型人群中没有代表。构建了一个丰富的群体 PK 模型，能够成功地描述年龄较小的儿童的 PK 特征。
我们得出结论，现有的 rFVIII-Fc 群体 PK 模型在≥12 岁的患者中是有效的。然而，它在年龄较小的患者中不可靠。我们的替代模型，由包括儿童在内的真实世界患者数据构建，允许更好地描述≥5 岁的患者。
