Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic\nstroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve\nthe obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective\nand it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we\npropose an efficient mathematical modelling approach that can be used to evaluate the therapeutic\nefficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines\nthe pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying\nthe drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing\nprotocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation\nresults are compared for temporal concentrations of fibrinolytic proteins in plasma and the time\nthat is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid\ndegradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily\nlead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in\nplasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal\nadministration regimen should be sought by keeping the tPA level sufficiently high throughout the\ntreatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic\nplasma. This can be achieved through model-based optimisation in the future.
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