Chelle Pierre, Yeung Cindy H T, Croteau Stacy E, Lissick Jennifer, Balasa Vinod, Ashburner Christina, Park Young Shil, Bonanad Santiago, Megías-Vericat Juan Eduardo, Nagao Azusa, Wynn Tung, Corrales-Medina Fernando, Tran Huyen, Sharathkumar Anjali, Chitlur Meera, Sarmiento Samuel, Edginton Andrea, Iorio Alfonso
School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada.
Clin Pharmacokinet. 2020 Feb;59(2):245-256. doi: 10.1007/s40262-019-00809-6.
Rurioctacog alfa pegol (Adynovate) is a modified recombinant factor VIII concentrate used for treating hemophilia A. Aiming to improve treatment tailoring on the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform for patients of all ages treated with Adynovate, we have developed and evaluated a population pharmacokinetic (PopPK) model. On the platform, PopPK models are used as priors for Bayesian forecasting that derive individual PK of hemophilia patients and are subsequently used for personalized dose regimen design.
Factor activity measurements and demographic covariate data from patients infused with Adynovate were extracted from the WAPPS-Hemo database. Evaluations testing the appropriateness of Bayesian forecasting included 10-fold cross validation, a limited sampling analysis (LSA), and an external evaluation using additional independent data extracted from the WAPPS-Hemo database at a later date.
The model was constructed using 650 plasma factor activity observations (555 one stage assay and 95 chromogenic assay - 4.6% below limit of quantification) measured in 154 patients from 36 hemophilia centres. A two-compartment model including between subject variability on clearance and central volume was selected as the base model. Covariates were fat free mass on clearance and central volume, age on clearance and assay type on activity. The final model was well-suited to predict PK parameters of new individuals (n = 26) from sparse observations.
The development of a PopPK model for Adynovate using real-world data increases the covariate space (e.g. age) beyond what is possible from clinical trial data. This model is available on the WAPPS-Hemo platform for tailoring treatment in hemophilia A patients.
聚乙二醇化重组凝血因子VIII（Adynovate）是一种经过修饰的重组凝血因子VIII浓缩物，用于治疗A型血友病。为了改进可通过网络访问的血友病群体药代动力学服务平台（WAPPS-Hemo）上针对接受Adynovate治疗的所有年龄段患者的治疗方案定制，我们开发并评估了一个群体药代动力学（PopPK）模型。在该平台上，PopPK模型被用作贝叶斯预测的先验模型，用于推导血友病患者的个体药代动力学参数，随后用于个性化给药方案设计。
从WAPPS-Hemo数据库中提取接受Adynovate输注患者的因子活性测量值和人口统计学协变量数据。测试贝叶斯预测适用性的评估包括10倍交叉验证、有限采样分析（LSA）以及使用稍后从WAPPS-Hemo数据库中提取的额外独立数据进行的外部评估。
该模型使用了来自36个血友病中心的154名患者的650次血浆因子活性观测值构建（555次单步测定和95次显色测定 - 低于定量下限4.6%）。选择了一个两室模型作为基础模型，该模型包括清除率和中央室容积的个体间变异性。协变量为清除率和中央室容积的去脂体重、清除率的年龄以及活性的测定类型。最终模型非常适合从稀疏观测值预测新个体（n = 26）的药代动力学参数。
使用真实世界数据开发Adynovate的PopPK模型扩展了协变量空间（如年龄），超出了临床试验数据所能提供的范围。该模型可在WAPPS-Hemo平台上用于为A型血友病患者定制治疗方案。
