Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.
Brain Korea 21 plus Project for Medical Science, Yonsei University, Seoul, South Korea.
Br J Clin Pharmacol. 2018 Nov;84(11):2586-2599. doi: 10.1111/bcp.13715. Epub 2018 Aug 21.
Recombinant tissue plasminogen activator (rt-PA) is the only first-line agent approved by the US Food and Drug Administration to treat acute ischaemic stroke. However, it often causes the serious adverse event (AE) of haemorrhagic transformation. The present study developed a pharmacometric model for the rt-PA treatment effect and AE and, using the developed model, proposed a benefit-to-risk ratio assessment scheme as a supportive tool to optimize treatment outcome.
The data from 336 acute ischaemic stroke patients were used. The treatment effect was assessed based on an improvement in National Institutes of Health Stroke Scale (NIHSS) scores, which were described using an item response theory (IRT)-based disease progression model. Treatment failure and AE probabilities, and their occurrence times, were described by incidence and time-to-event models. Using the developed model, benefit-to-risk ratios were simulated under various scenarios using the global benefit-to-risk trade-off ratio (GBR).
High initial NIHSS score and middle cerebral artery (MCA) stroke were risk factors for treatment failure, where the failure rate with MCA stroke was 2.87-fold higher than with non-MCA stroke. The haemorrhagic transformation time was associated with longitudinal changes in NIHSS scores. The benefit-to-risk ratio simulated was highest in minor stroke severity, with GBR >1 in all scenarios, and the ratio with non-MCA stroke was 2-3 fold higher than with MCA stroke.
The study demonstrated the feasibility of applying an IRT model to describing the time course of the rt-PA treatment effect and AE. Benefit-to-risk ratio analyses showed that the treatment was optimal in non-MCA stroke with minor stroke severity.
重组组织型纤溶酶原激活剂（rt-PA）是唯一经美国食品和药物管理局批准用于治疗急性缺血性脑卒中的一线药物。然而，它常导致严重的不良事件（AE）——出血性转化。本研究建立了 rt-PA 治疗效果和 AE 的药代动力学模型，并使用所建立的模型提出了一种获益-风险比评估方案，作为优化治疗结果的辅助工具。
使用了 336 例急性缺血性脑卒中患者的数据。采用基于项目反应理论（IRT）的疾病进展模型描述国立卫生研究院卒中量表（NIHSS）评分的改善，以此评估治疗效果。采用发生率和时间事件模型描述治疗失败和 AE 的概率及其发生时间。使用所建立的模型，通过全球获益-风险权衡比（GBR）在各种场景下模拟获益-风险比。
较高的初始 NIHSS 评分和大脑中动脉（MCA）卒中是治疗失败的风险因素，MCA 卒中的失败率是无 MCA 卒中的 2.87 倍。出血性转化时间与 NIHSS 评分的纵向变化相关。模拟的获益-风险比在轻度脑卒中严重程度下最高，所有场景中 GBR>1，无 MCA 卒中的比率是 MCA 卒中的 2-3 倍。
本研究表明应用 IRT 模型描述 rt-PA 治疗效果和 AE 的时间过程是可行的。获益-风险比分析表明，在轻度脑卒中且非 MCA 卒中时，治疗效果最佳。
