(95) A Novel Delivery-Platform Reduces Cardiac Toxicity of the FDA-approved BTK Inhibitors used in Blood Malignancies

Objective : The goal of the current work is to evaluate the use of a novel drug delivery platform primarily based on using the new polymeric materials Soluplus as a promising strategy to combat the current clinical limitations of the FDA-approved BTK inhibitors used in blood malignancies. More specifically, the cardiac toxicities patients encounter while on these medications.

Methods: The new drug delivery platform was developed using a simple solid dispersion methodology. Briefly, ACS-chemical grade APIs of the two recently FDA-approved BTK inhibitors, Acalabrutinib and Zanubrutinib, were mixed with Soluplus in an clinically EMA-approved ratio. Acetone was then added to the mixtures, and mixed till completely solubilized. Acetone was dried out, and then a warm water was added followed by agitation/ homogenization. Several concentrations of the APIs were prepared in a range of 10 µM-160 µM. Employing the Invitrogen™ Predictor™ hERG Fluorescence Polarization Assay Kit, these APIs concentrations as well as negative and positive controls as provided by the kit were tested using a fluorescence plate reader. This assay provides an efficient method for determining whether test compounds block the hERG channel or not.

Results: The preliminary data indicates that the new delivery platform using Soluplus produced a high fluorescence polarization compared to the APIs without the platform in a concentration dependent manner. Reflecting the ability of the platform to reduce the binding potential of these APIs to the hERG channel, and thus causing the unwanted cardiac toxicity.

Conclusions: The data from the current work open the door toward the necessity of keeping exploring the new and emerging excipients as a way to optimize the safety profiles of the recent highly effective targeted cancer therapies such BTK inhibitors.