In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke

• Published in: Computers in biology and medicine 2024-03, Vol.171, p.108141, Article 108141
• Main Authors: Yang, Yilin, Gu, Boram, Xu, Xiao Yun
• Format: Article
• Language: English
• Subjects: Adsorption; Bats; Binding sites; Clinical trials; Combination therapy; Computational model; Depletion; Drug dosages; Fibrinogen; Fibrinogen - pharmacology; Fibrinogen - therapeutic use; Fibrinolysis; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - therapeutic use; Heart attacks; Hemorrhage; Humans; Intravenous administration; Ischemia; Ischemic Stroke; Lysis; Mutants; Pharmacodynamics; Pharmacokinetics; Plasma; Pro-urokinase; Reaction mechanisms; Recombinant Proteins; Risk reduction; Simulation; Stroke; Stroke - drug therapy; Stroke - etiology; t-Plasminogen activator; Therapy; Thrombolysis; Thrombolytic Therapy - adverse effects; Thrombolytic Therapy - methods; Tissue plasminogen activator; Tissue Plasminogen Activator - adverse effects; Tissue Plasminogen Activator - therapeutic use; U-Plasminogen activator; Urokinase; Urokinase-Type Plasminogen Activator; Veins & arteries
• ISSN: 0010-4825; 1879-0534; 1879-0534
• DOI: 10.1016/j.compbiomed.2024.108141

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. •First in-silico model of combination therapy with alteplase and pro-urokinase.•Coupled modelling of systemic PK-PD and local fibrinolysis for stroke therapy.•Simulation results for different combinations of alteplase and pro-urokinase.•Increasing pro-urokinase dose can improve lysis rate; no negative impact on safety.•Model can help with future optimization of dose regimen for dual therapy.