School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada.
Department of Health Research Methods, Evidence and Impact and Department of Medicine, McMaster University, Ontario, Canada.
J Thromb Haemost. 2022 Sep;20(9):2012-2021. doi: 10.1111/jth.15803. Epub 2022 Jul 7.
Hemophilia A is a bleeding disorder characterized by a deficiency of a coagulation factor VIII and optimally treated using pharmacokinetics (PK)-guided prophylactic replacement therapy. To decrease patient burden, PK can be estimated from sparse sampling leveraging population PK modeling. However, recommendations for sampling times meant for patients with hemophilia A as a group may not be optimal at the individual level.
To evaluate a personalized limited sampling approach (Personalized LSA) that suggests a next sampling time point that would provide a more accurate estimation of terminal half-life of FVIII concentrates when using a population PK approach.
331 PK studies with rich sampling were extracted from the WAPPS-Hemo database. Two sampling approaches were evaluated and compared: 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected using the personalized LSA prediction; 974 PK studies consisting of two samples were built from the rich sampling data including one sample selected randomly. Half-life values were estimated on the sparse data and compared within patients to the estimates obtained on the rich data for assessing the error on half-life values.
Relative errors between estimates from sparse sampling data using personalized LSA and from rich sampling data were always lower than 20% and significantly lower than the comparative approach that used random sampling (median-95th percentile were 3.8%-13.1% vs. 7.0%-23.5%, respectively, p-value < 10 ). Moreover, less than 4% of the samples suggested by the personalized LSA were below the limit of quantification.
Identifying the most informative sampling points for PK assessment using a Personalized LSA approach that accounts for individual differences in PK improves the precision of FVIII terminal half-life estimates in sparse sampling.
血友病 A 是一种出血性疾病，其特征是凝血因子 VIII 缺乏，最佳治疗方法是采用药代动力学（PK）指导的预防性替代疗法。为了降低患者负担，可以利用群体 PK 模型从稀疏采样中估算 PK。然而，针对血友病 A 患者群体的采样时间建议在个体水平上可能并不最佳。
评估一种个性化有限采样方法（Personalized LSA），该方法建议下一个采样时间点，以便在使用群体 PK 方法时更准确地估计 FVIII 浓缩物的终末半衰期。
从 WAPPS-Hemo 数据库中提取了 331 项具有丰富采样的 PK 研究。评估并比较了两种采样方法：974 项 PK 研究由丰富采样数据构建，包括使用个性化 LSA 预测选择的一个样本；974 项 PK 研究由丰富采样数据构建，包括随机选择的一个样本。在稀疏数据上估计半衰期值，并在患者内与丰富数据上获得的估计值进行比较，以评估半衰期值的误差。
使用个性化 LSA 从稀疏采样数据中估算的半衰期值与从丰富采样数据中估算的半衰期值之间的相对误差始终低于 20%，且显著低于使用随机采样的比较方法（中位数-95%分位数分别为 3.8%-13.1%比 7.0%-23.5%，p 值<0.001）。此外，个性化 LSA 建议的样本中少于 4%低于定量下限。
使用个性化 LSA 方法确定 PK 评估最具信息性的采样点，该方法考虑了 PK 个体差异，可提高 FVIII 终末半衰期在稀疏采样中的估算精度。
