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Combining mathematical modelling with in vitro experiments to predict in vivo drug-eluting stent performance

McKittrick, Craig M. and McKee, Sean and Kennedy, Simon and Oldroyd, Keith and Wheel, Marcus and Pontrelli, Giuseppe and Dixon, Simon and McGinty, Sean and McCormick, Christopher (2019) Combining mathematical modelling with in vitro experiments to predict in vivo drug-eluting stent performance. Journal of Controlled Release, 303. pp. 151-161. ISSN 0168-3659

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    Abstract

    In this study, we developed a predictive model of in vivo stent based drug release and distribution that is capable of providing useful insights into performance. In a combined mathematical modelling and experimental approach, we created two novel sirolimus-eluting stent coatings with quite distinct doses and release kinetics. Using readily measurable in vitro data, we then generated parameterised mathematical models of drug release. These were then used to simulate in vivo drug uptake and retention. Finally, we validated our model predictions against data on drug kinetics and efficacy obtained in a small in vivo evaluation. In agreement with the in vivo experimental results, our mathematical model predicted consistently higher sirolimus content in tissue for the higher dose stents compared with the lower dose stents. High dose stents resulted in statistically significant improvements in three key efficacy measures, providing further evidence of a basic relationship between dose and efficacy within DES. However, our mathematical modelling suggests a more complex relationship is at play, with efficacy being dependent not only on delivering an initial dose of drug sufficient to achieve receptor saturation, but also on the consequent drug release rate being tuned to ensure prolonged saturation. In summary, we have demonstrated that our combined in vitro experimental and mathematical modelling framework may be used to predict in vivo DES performance, opening up the possibility of an in silico approach to optimising the drug release profile and ultimately the effectiveness of the device.