TCT 2019: Identifying Conditions for Very Late Tissue Retention of Paclitaxel: Insights from Mechanistic Computational Modeling

Rami Tzafriri, Sahil A. Parikh, Juan Granada, Elazer R. Edelman. “Identifying Conditions for Very Late Tissue Retention of Paclitaxel: Insights from Mechanistic Computational Modeling.”

Background: A recent meta-analysis of randomized controlled trials investigating paclitaxel-coated balloons and stents in the femoral and/or popliteal arteries reported an increased risk of death 2-5 years after treatment. Yet, no mechanisms for mortality have been offered and preclinical experiments suggest drug clearance by one year.

Methods: We developed a mechanistic 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. This concentration was predicted based on equations of 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.

Results: Numerical simulations demonstrated that dissolution of delivered anhydrous paclitaxel coating in porcine iliofemorals is complete within 45 days, and resolved the contribution of tissue-retained dissolved paclitaxel. Tissue retention of dissolved paclitaxel is predicted to be dominated by high affinity-bound drug and the 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.

Conclusion: Computational modeling implicates slow diffusivity (typical of calcified lesions) and microtubule overexpression (as seen in diseased/injured/inflamed arteries) as scenarios of extended paclitaxel tissue retention years after initial coating-tissue contact.

Presented at TCT 2019, September 25-29, San Francisco, CA.