Gu Boram, Piebalgs Andris, Huang Yu, Longstaff Colin, Hughes Alun D, Chen Rongjun, Thom Simon A, Xu Xiao Yun
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Biotherapeutics Section, National Institute for Biological Standards and Control, South Mimms, Hertfordshire EN6 3QG, UK.
Pharmaceutics. 2019 Mar 7;11(3):111. doi: 10.3390/pharmaceutics11030111.
Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic stroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve the obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective and it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we propose an efficient mathematical modelling approach that can be used to evaluate the therapeutic efficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines the pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying the drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing protocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation results are compared for temporal concentrations of fibrinolytic proteins in plasma and the time that is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid degradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily lead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in plasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal administration regimen should be sought by keeping the tPA level sufficiently high throughout the treatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic plasma. This can be achieved through model-based optimisation in the future.
溶栓治疗是急性缺血性卒中（AIS）治疗中的医疗程序之一，即通过静脉注射组织纤溶酶原激活剂（tPA）来溶解阻塞性血凝块。通过溶栓治疗AIS有时可能无效，并且会引起严重并发症，如颅内出血（ICH）。在本研究中，我们提出了一种有效的数学建模方法，可用于评估在各种临床相关情况下溶栓治疗的疗效和安全性。我们的模型将tPA的药代动力学和药效学与局部血凝块溶解动力学相结合。以美国食品药品监督管理局（FDA）批准的给药方案为参考，通过改变药物剂量、推注-输注延迟时间和推注-输注比例，我们使用该模型模拟了13种给药方案。比较了血浆中纤溶蛋白的时间浓度和实现再通所需时间的模拟结果。我们的结果表明，高输注速率会导致血浆纤维蛋白原快速降解，这表明ICH风险增加，但不一定会导致快速再通。此外，推注-输注延迟会导致血浆tPA浓度立即下降，从而延长实现再通的时间。因此，应寻求一种最佳给药方案，在整个治疗过程中保持tPA水平足够高，同时最大化溶解速率，同时限制全身血浆中纤维蛋白原的降解。这可以通过未来基于模型的优化来实现。
