Department of Chemical Engineering, Imperial College London, London, SW7 2AZ, United Kingdom.
School of Chemical Engineering, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, Republic of Korea.
Comput Biol Med. 2024 Mar;171:108141. doi: 10.1016/j.compbiomed.2024.108141. Epub 2024 Feb 13.
The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 μM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 μM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.
组织型纤溶酶原激活物（tPA）与前尿激酶（proUK）联合溶栓的协同优势已在多项体外实验中得到证实，并且开发了一种单一位点 proUK 突变体（m-proUK）以提高其在血浆中的稳定性。基于这些研究，静脉内 tPA 和 m-proUK 的联合溶栓治疗被认为是缺血性脑卒中患者的一种有前途的治疗方法。本文通过将药代动力学和药效学的计算模拟与局部纤维蛋白溶解模型相结合，评估了这种双重治疗的疗效和安全性。模拟了七种剂量方案，并与标准的静脉内 tPA 单一疗法进行了比较。我们的模拟结果提供了更多关于 tPA 和 m-proUK 在血栓溶解过程中的互补反应机制的见解，并表明双重治疗可以达到与 tPA 单一疗法相似的再通时间（约 50 分钟），同时使循环纤维蛋白原水平保持在正常范围内。具体而言，我们的结果表明，对于所有含有 5mg tPA 推注剂量的双重治疗方案，在 50 分钟缓慢消耗后，纤维蛋白原的血浆浓度稳定在 7.5μM 左右，而标准 tPA 治疗则观察到循环纤维蛋白原的快速消耗（至 5μM），表明双重治疗在降低颅内出血风险方面具有潜在优势。通过对不同剂量组合的模拟发现，增加 tPA 推注量可以显著影响纤维蛋白原水平，但只能适度改善再通时间。相反，m-proUK 剂量和输注时间对纤维蛋白原水平的影响较小，但对再通时间的影响较大。因此，未来的剂量方案优化应侧重于限制 tPA 推注量，同时调整 m-proUK 剂量和输注速率。这些调整可能会最大限度地发挥这种联合治疗方案在缺血性脑卒中治疗中的治疗优势。
