A pharmacokinetic–pharmacodynamic (PK‐PD) approach is developed for modelling the recurrent bleeding events in patients with severe haemophilia to investigate the relationship between factor VIII plasma activity level and the instantaneous risk of a bleed. The model incorporates patient‐level pharmacokinetic (PK) information obtained through measurements taken prior to the study which are used to fit a non‐linear mixed‐effects two‐compartment PK model. Dosing times within the study are combined with the PK model to provide the estimated factor VIII plasma level for all patients, which is used as a time‐dependent covariate within the recurrent events model. Methods are developed to correct the attenuation in covariate effects that would otherwise arise due to the discrepancy between estimated and true factor VIII. In contrast to existing methods proposed for such data, such as count data regression or time‐to‐event analysis, the new method allows all the bleeding times to be used to investigate the relationship between current factor VIII and risk of a bleed. The performance of the proposed estimators are assessed via simulation and found to outperform the naive estimator, which treats the estimated factor VIII levels as if they were measured without error, both in terms of bias and mean squared error.

中文翻译：

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血友病出血事件的复发事件建模

开发了一种药代动力学-药效学（PK-PD）方法来模拟重度血友病患者的复发性出血事件，以研究VIII因子血浆活性水平与瞬时出血风险之间的关系。该模型包含通过研究前获得的测量结果获得的患者水平的药代动力学（PK）信息，这些信息用于拟合非线性混合效应两室PK模型。将研究中的给药时间与PK模型相结合，为所有患者提供估计的VIII因子血浆水平，将其用作复发事件模型中随时间变化的协变量。已开发出方法来校正因估计因子VIII与实际因子VIII之间的差异而导致的协变量效应的衰减。与针对此类数据提出的现有方法（例如计数数据回归或事件发生时间分析）相比，该新方法允许将所有出血时间用于调查当前因素VIII与出血风险之间的关系。通过仿真评估拟议估算器的性能，发现其性能优于单纯估算器，朴素估算器将估算的VIII因子水平视为就其误差和均方误差而言，均已测量为无误差。