Computational Model Suggests a New Paradigm for Accelerated Treatment Optimization With Paclitaxel Devices

August 28, 2019—CBSET announced that its scientists have published data and analyses that provide critical insights into the interplay between target anatomy and device attributes in determining balloon- and stent-based paclitaxel retention in healthy and diseased arteries. According to CBSET, these findings may transform the understanding of the safety and efficacy of paclitaxel-coated devices used in the treatment of peripheral artery disease.

The article, “Taking Paclitaxel Coated Balloons to a Higher Level: Predicting Coating Dissolution Kinetics, Tissue Retention and Dosing Dynamics,” by Abraham R. Tzafriri, PhD; Sahil A. Parikh, MD; and Elazer R. Edelman, MD, is available in Journal of Controlled Release (2019;310:94–102).

Based in Lexington, Massachusetts, CBSET is a not-for-profit preclinical research institute dedicated to biomedical research, education, and advancement of medical technologies. Dr. Tzafriri is CBSET’s Director of Research and Innovation. Dr. Edelman is Chairman and Cofounder of CBSET.

Dr. Parikh, who is Director of Endovascular Services at the Columbia University College of Physicians and Surgeons in New York, New York, commented in the announcement, “The recent controversy regarding a possible increase in risk for mortality after treatment with paclitaxel-coated balloons and stents at 2 and 5 years posttreatment has raised concerns regarding the clinical paradigm for evaluating these devices, while also highlighting the lack of a fundamental understanding of how these devices deliver and retain drugs in the artery and at what concentrations.”

He continued, “This mechanistic model empowers and reassures clinicians about the amount of active paclitaxel that our patients are exposed to, while offering insights and a framework for accelerating the preclinical development of new technologies such as those including sirolimus.”

Dr. Tzafriri added, “Our past research has focused on these very issues, defining the roles of drug lipophilicity and size as well as lesion composition. What was lacking was a framework for integrating such experimental data and coupling it to models of coating dissolution. By doing just this, the current study provides novel insights into local drug retention and tissue dosing after treatment with drug-coated devices. Tissue retention dynamics are now understood as comprising three primary phases: luminal coating dissolution, tissue embedded coating dissolution, and receptor dissociation, with the latter determining the rate of terminal clearance. Receptor expression in healthy porcine tissue is similar for paclitaxel and sirolimus but can be elevated by injury and disease. Moreover, simulations predict that tissue mineralization, which was previously identified as a hindrance to arterial drug distribution, can also hinder the dissociation of receptor-bound drug and provide a mechanism for multiyear drug retention.”

Finally, Dr. Edelman noted, “Mechanistic insight bridges the preclinical and clinical experiences and is ultimately the only effective means of resolving seeming conflicts or disparities in observations. The groundbreaking work reported herein builds upon a wealth of hands-on experience with these devices and over 20 years of NIH-funded fundamental research in endovascular drug delivery to provide the precision needed to produce a coherent paradigm by which to appreciate this complex field. As we move forward, it is incumbent upon us to continue to employ and develop these tools, to help industry and regulators develop safer and more efficacious therapies.”