Tzafriri AR. “Multiyear Tissue Retention of Paclitaxel is Driven by Lesion Complexity: Insights from Experimentally Grounded Computational Modeling“
A recent meta-analysis of randomized controlled trials investigating paclitaxel-coated balloons and stents in femoropopliteal arteries reported increased mortality risk 2-5 years after treatment, with no causal mechanism.
We developed an experimentally grounded computational model to identify scenarios of very late paclitaxel tissue retention. The model accounted for paclitaxel coating dissolution based on solubility, surface area and dissolution rate constant, while accounting for the role of soluble drug concentration at the dissolution boundary layer, extracellular diffusion and low affinity binding, cell uptake and high affinity binding to receptors using physiologically-realistic parameter estimates. Analysis of published data on crystalline paclitaxel (anhydrous and dihydrate) coated balloons revealed that drug release from material deposited in these arteries is reaction-controlled and allowed for estimation of associated dissolution rate constants.
Simulations demonstrated that dissolution of delivered anhydrous paclitaxel coating in porcine iliofemorals is complete within 45 days, and that dissolved paclitaxel is predominantly retained via specific binding to microtubules. Consequently, terminal clearance half-life increases linearly with receptor density and the degree of diffusive hindrance. By contrast, delivered dose can extend the duration of coating dissolution and maximal dosing, but not the subsequent clearance rate which is lesion dependent.
Calcification and microtubule overexpression in diseased/injured/inflamed arteries both emerge as scenarios of extended paclitaxel tissue retention years after initial coating-tissue contact. These data provide a mechanism for specific inhibition of hyperplasia but specifically contravene the possibility of a dose dependent mortality as retention is dominated by specific pharmacological binding.
Poster presentation at ICI 2019, December 8-10, Tel Aviv, Israel.