Teffera Yohannes, Tippin Tim, Bartkus Angela, de Castro Francine A, Faison Shamia L, Morrison Marion, Mullin Mark J, Naderer Odin
Chimerix, Inc., Durham, NC, USA.
Certara Strategic Consulting, Princeton, NJ, USA.
Clin Pharmacol Drug Dev. 2025 Apr 17. doi: 10.1002/cpdd.1541.
Dordaviprone (ONC201) is a novel, small-molecule imipridone with antitumor activity in patients with a glioma. Six healthy male participants received a single 625-mg (100-µCi) oral dose of [C]-dordaviprone. Blood, plasma, urine, and feces were collected up to 288 hours after dosing and analyzed by liquid scintillation counting. Metabolite profiles were evaluated using liquid chromatography-radiometric detection, and metabolite identification was accomplished by liquid chromatography with tandem mass spectrometry. Concentrations of drug-derived radioactivity in blood and plasma peaked at 1 hour after dosing and were below the limit of quantitation by 72 hours (whole blood) to 96 hours (plasma) after dosing. Seventy-one percent of the administered radioactivity was recovered in urine and 20% in feces. In plasma, the major circulating compounds were dordaviprone and the inactive metabolite ONC207, each contributing approximately one third of the total radioactivity area under the curve. Of the 19 metabolites identified in plasma, no other single metabolite contributed more than 10% to the total radioactivity area under the curve. Unchanged dordaviprone was a minor component in excreta (less than 0.3%), with multiple metabolites identified in urine and feces. Given the lack of dordaviprone in excreta and the metabolites formed, the primary route for dordaviprone elimination was through urinary excretion of oxidative metabolites.
多达维普隆（ONC201）是一种新型小分子咪吡啶酮，对神经胶质瘤患者具有抗肿瘤活性。6名健康男性受试者口服了单次625毫克（100微居里）的[C] - 多达维普隆。给药后长达288小时收集血液、血浆、尿液和粪便，并通过液体闪烁计数法进行分析。使用液相色谱 - 放射性检测评估代谢物谱，并通过液相色谱 - 串联质谱法完成代谢物鉴定。血液和血浆中药物衍生的放射性浓度在给药后1小时达到峰值，给药后72小时（全血）至96小时（血浆）低于定量限。71%的给药放射性在尿液中回收，20%在粪便中回收。在血浆中，主要的循环化合物是多达维普隆和无活性代谢物ONC207，它们各自对曲线下总放射性面积的贡献约为三分之一。在血浆中鉴定出的19种代谢物中，没有其他单一代谢物对曲线下总放射性面积的贡献超过10%。未变化的多达维普隆是排泄物中的次要成分（小于0.3%），在尿液和粪便中鉴定出多种代谢物。鉴于排泄物中缺乏多达维普隆以及形成的代谢物，多达维普隆消除的主要途径是通过氧化代谢物的尿液排泄。
