Identification of degradation products and molecular mechanism using experimental and theoritical approchaes: application to oral solution formulation; case of ONC201 in diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive forms of brain tumor, a rare disease that mainly affects children with an incidence peak around 7. ONC201 is a new drug substance which can cross the blood-brain barrier to antagonize type 2 dopamine receptor and to induce TNF-related apoptosis-inducing ligand (TRAIL). This molecule has shown encouraging results in the treatment of DIPG. However, the only dosage forms available at the moment are capsules, limiting their use for children under 6. There is therefore a great need to develop pediatric forms of ONC201.
Then, to control the quality and safety conditions inherent in this academic manufacturing process, while there is virtually no data available to date to understand the stability of ONC201, we had to determine the stability profile of ONC201. We found at that ONC201 is sensitive to light and oxidation and we identified the molecular structures of the main degradation products formed by liquid chromatography–high-resolution mass spectrometry. The second step of our work was to identify how these degradation products were formed and which conditions favor their formation in an aqueous environment. For that, we used data from ab initio calculations and experimental work to supplement the structural information. An acidic environment, (pH < 4) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. The last step of this work was to characterize ONC 201 behavior in aqueous solution to optimize its behavior and we found at that ONC solubility is too low, and can form a eutectic with nicotinamide, a hydrotropic agent, increasing its solubility by a factor of 2. All these data were used to optimize the formulation of an oral solution adapted to pediatric clinical needs in DIPG and could thus be integrated into our hospital’s compassionate program.