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Pharmaceutics. 2019 Mar 7;11(3). pii: E111. doi: 10.3390/pharmaceutics11030111.

Mathematical Modelling of Intravenous Thrombolysis in Acute Ischaemic stroke: Effects of Dose Regimens on Levels of Fibrinolytic Proteins and Clot Lysis Time.

Author information

1
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. b.gu13@imperial.ac.uk.
2
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. andris.piebalgs@outlook.com.
3
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. y.huang@imperial.ac.uk.
4
Biotherapeutics Section, National Institute for Biological Standards and Control, South Mimms, Hertfordshire EN6 3QG, UK. Colin.Longstaff@nibsc.org.
5
Institute of Cardiovascular Science, University College London, London WC1E 6DD, UK. alun.hughes@ucl.ac.uk.
6
MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK. alun.hughes@ucl.ac.uk.
7
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. rongjun.chen@imperial.ac.uk.
8
National Heart & Lung Institute, Imperial College London, Hammersmith Campus, London W12 0NN, UK. s.thom@imperial.ac.uk.
9
Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. yun.xu@imperial.ac.uk.

Abstract

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.

KEYWORDS:

acute ischaemic stroke; mathematical modelling; pharmacodynamics; pharmacokinetics; thrombolysis; tissue plasminogen activator

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