ABSTRACT:
Vonoprazan is a potassium-competitive acid blocker widely used for the management of acid-related gastrointestinal disorders. Although the chemical structures of vonoprazan have been elucidated, a systematic toxicological evaluation has not been reported in public literature. In the present study, an in-silico toxicological risk assessment was conducted for two major degradation products of vonoprazan namely N-dealkylated vonoprazan (DP1) and vonoprazan aldehyde (DP2) using QSAR methodologies recommended under ICH M7(R2) for mutagenicity assessment, along with additional evaluation of other toxicity endpoints for broader toxicological understanding. A complementary quantitative structure-activity relationship (QSAR) strategy was employed, as recommended under ICH M7(R2), integrating statistical-based predictions (ADMETlab), expert rule-based structural alert analysis (ToxTree), and additional consensus modeling using the Online Chemical Modeling Environment (OCHEM). Mutagenicity, carcinogenicity, and selected organ toxicity endpoints were evaluated for the intact degradation products as well as relevant structural fragments. DP1 was consistently predicted to be non-mutagenic and non-carcinogenic across all applied models and was therefore classified as an ICH M7 Class 5 (non-mutagenic) impurity, permitting control under standard ICH Q3B(R2) limits. In contrast, DP2 triggered structural alerts for potential genotoxicity due to the presence of an aldehyde functionality and was classified as an ICH M7 Class 3 impurity. However, in-silico metabolic assessment indicated rapid oxidation of DP2 to the corresponding carboxylic acid metabolite, which was devoid of genotoxic and carcinogenic alerts, supporting a mitigated toxicological risk. This study establishes a robust, toxicological framework aligned with ICH M7(R2) principles for mutagenicity assessment for the safety evaluation and control of vonoprazan degradation products and provides a scientifically justified basis for impurity specification setting and regulatory risk management in pharmaceutical development.