Certara QSP-UK, Canterbury, UK.
Schrodinger Inc., New York City, New York, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Apr;12(4):444-461. doi: 10.1002/psp4.12912. Epub 2023 Jan 20.
Antibody-mediated removal of aggregated β-amyloid (Aβ) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aβ monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aβ and Aβ aggregation and clearance of aggregated Aβ by activated microglia cells, which is enhanced by the interaction of antibody-bound Aβ. The model allows for the prediction of Aβ positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aβ and plasma Aβ /Aβ ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aβ /Aβ ratio while slightly overestimating the change in CSF Aβ . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.
抗体介导的聚集β-淀粉样蛋白（Aβ）清除是目前最先进的、具有临床潜力的阿尔茨海默病疾病修饰治疗方法。我们描述了一种定量系统药理学（QSP）方法，用于使用 Aβ 的详细微观模型来描述 Aβ 单体、寡聚体、原纤维和斑块的动力学，以及通过与抗体结合的 Aβ相互作用增强的活化小胶质细胞清除聚集的 Aβ。该模型允许预测 Aβ 正电子发射断层扫描（PET）成像负荷，其通过标准化摄取值比来衡量。一个基于生理学的药代动力学模型被无缝集成，以描述单克隆抗体的靶标暴露，并模拟脑脊液（CSF）和血浆生物标志物的动力学，包括 CSF Aβ 和血浆 Aβ/Aβ 比值生物标志物。载脂蛋白 E 基因型作为小胶质细胞清除的差异来实现。通过在血管周围隔室中纳入与抗体结合的、斑块介导的巨噬细胞激活，该模型还预测了淀粉样蛋白相关成像异常伴水肿（ARIA-E）的发生率。QSP 平台通过与 aducanumab、bapineuzumab、crenezumab、gantenerumab、lecanemab 和 solanezumab 的药理学和临床信息进行校准，充分预测了 PET 成像测量的淀粉样蛋白负荷变化和血浆 Aβ/Aβ 比值变化，同时略微高估了 CSF Aβ 的变化。除了 bapineuzumab 外，所有抗体的 ARIA-E 都得到了很好的预测。该 QSP 模型可以支持不同淀粉样蛋白调节干预的临床试验设计，定义最佳滴定和维持方案，并为理解临床实践中生物标志物反应的可变性提供了第一步。
