Development of a pediatric oral solution of ONC201 using nicotinamide to enhance solubility and stability

Abstract

Diffuse intrinsic pontine glioma (DIPG) poses a significant treatment challenge in pediatric patients due to its aggressive nature and difficulty in crossing the blood-brain barrier with effective therapies. ONC201 (dordaviprone) shows promises in inducing apoptosis in cancer cells but suffers from poor water solubility and stability issues. Moreover, conventional solubilizing agents acceptable in formulations intended for adult patients are not suitable for pediatric use. So, this study aims to develop a stable, concentrated oral solution of ONC201 suitable for pediatric dosing without harmful excipients and efficient taste masking. Based on Molecular Dynamics simulations, a first screening among a selection of hydrotropes was carried out and, from the results obtained, nicotinamide was selected for experimental study. Given ONC201's challenges of poor solubility and stability, the formulation's physical and chemical properties were meticulously optimized. Extensive analyses, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and nuclear magnetic resonance (NMR) spectroscopy, confirmed the solution's stability across various storage conditions, with no evidence of precipitation or significant degradation. This newly formulated solution is now used inside daily practice in the French compassionate Use Program to give access to ONC201 allowing treating patients who suffer from swallowing disorders.

Keywords: Benzoic acid; Citric acid; Dordaviprone; Drug formulation; Drug solubility; Hydrotropes; Hydroxypropyl-β-cyclodextrin; Nicotinamide; ONC201; Pediatric formulation.