Toxicological insights and safety considerations of vorasidenib in grade 2 astrocytoma and oligodendroglioma

Abstract

Vorasidenib, a dual inhibitor of isocitrate dehydrogenase 1 and 2 (IDH1/2), has shown promise as a therapeutic agent following its recent FDA approval for the treatment of grade 2 astrocytomas and oligodendrogliomas harboring IDH mutations in patients 12 years of age and older following surgery. While Vorasidenib offers significant potential in targeting altered metabolic pathways in low-grade gliomas, its comprehensive toxicologic and safety profile has not been adequately explored. This research letter addresses this critical gap by presenting an in silico analysis of the potential toxicologic effects of Vorasidenib. Using computational tools - ADMETlab 3.0, FAF-Drugs 4.1, DeepPK, vNN-ADMET, Pred-hERG 5.0, ADVERPred, PreADMET, and ADMET-AI - and databases such as ChEMBL, PubChem, and ChemSpider, we evaluated the key physicochemical properties and predicted ADMET profiles of Vorasidenib, along with a comparative analysis of two other drugs, namely Ivosidenib and Enasidenib. Our results suggest potential risks associated with drug-induced liver injury (DILI) and hepatotoxicity, with structural properties indicative of hepatocellular damage during and after treatment. The low clearance rates associated with the low maximum recommended dose suggest that Vorasidenib may accumulate in the bloodstream over time, increasing the likelihood of toxic reactions. In addition, the predictive models indicate concerns for neurotoxicity, nephrotoxicity and cardiotoxicity, including potential blockade of hERG channels leading to QT interval prolongation and cardiac arrhythmias. Importantly, the analysis also indicates risks of genotoxicity and carcinogenicity, raising concerns about promoting additional tumor formation in patients already prone to malignancies. These results emphasize the need for further preclinical and clinical studies to validate the safety of Vorasidenib. A comprehensive understanding of the toxicologic profile is critical to ensure that the therapeutic benefit for patients with IDH1/2-mutated low-grade gliomas is not compromised by potential adverse effects. Careful monitoring of patients and tailored therapeutic strategies are essential to optimize clinical outcomes and guide physicians in the safe use of Vorasidenib in clinical practice.

Keywords: IDH 1/2 inhibition; toxicity; vorasidenib.

Figure 1.

Physicochemical and ADMET descriptors of Vorasidenib utilizing data from webservers and databanks. A radar plot depicting some of the main physicochemical properties is presented on the left. On the right, the molecule’s 2D structure with some of its main ADMET attributes, with blue denoting properties that are within reference values, and red denoting potential toxicity.