Takeda Development Center Americas, Inc., Lexington, Massachusetts
Takeda Development Center Americas, Inc., Lexington, Massachusetts.
Drug Metab Dispos. 2022 Jul;50(7):989-997. doi: 10.1124/dmd.122.000842. Epub 2022 May 3.
Metabolism and disposition of pevonedistat, an investigational, first-in-class inhibitor of the NEDD8-activating enzyme (NAE), were characterized in patients with advanced solid tumors after intravenous infusion of [C]pevonedistat at 25 mg/m (∼60-85 Ci radioactive dose). More than 94% of the administered dose was recovered, with ∼41% and ∼53% of drug-related material eliminated in urine and feces, respectively. The metabolite profiles of [C]pevonedistat were established in plasma using an accelerator mass spectrometer and excreta with traditional radiometric analysis. In plasma, unchanged parent drug accounted for approximately 49% of the total drug-related material. Metabolites M1 and M2 were major (>10% of the total drug-related material) circulating metabolites and accounted for approximately 15% and 22% of the drug-related material, respectively. Unchanged [C]pevonedistat accounted for approximately 4% and 17% of the dose in urine and feces, respectively. Oxidative metabolites M1, M2, and M3 appeared as the most abundant drug-related components in the excreta and represented approximately 27%, 26%, and 15% of the administered dose, respectively. Based on the unbound plasma exposure in cancer patients and in vitro NAE inhibition, the contribution of metabolites M1 and M2 to overall in vivo pharmacological activity is anticipated to be minimal. The exposure to these metabolites was higher at safe and well tolerated doses in rat and dog (the two preclinical species used in toxicology evaluation) plasma than that observed in human plasma. Reaction phenotyping studies revealed that CYP3A4/5 are primary enzymes responsible for the metabolic clearance of pevonedistat. SIGNIFICANCE STATEMENT: This study details the metabolism and clearance mechanisms of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, after intravenous administration to patients with cancer. Pevonedistat is biotransformed to two major circulating metabolites with higher exposure in nonclinical toxicological species than in humans. The pharmacological activity contribution of these metabolites is minimal compared to the overall target pharmacological effect of pevonedistat. Renal clearance was not an important route of excretion of unchanged pevonedistat (∼4% of the dose).
在静脉输注[C]pevonedistat（25mg/m，约 60-85 Ci 放射性剂量）后，对晚期实体瘤患者进行了研究性、首创的 NEDD8-激活酶（NAE）抑制剂 pevonedistat 的代谢和处置研究。给予的剂量超过 94%被回收，分别有∼41%和∼53%的药物相关物质经尿液和粪便消除。使用加速器质谱仪和传统放射性分析在血浆和排泄物中建立了[C]pevonedistat 的代谢物图谱。在血浆中，未改变的母体药物约占总药物相关物质的 49%。代谢物 M1 和 M2 是主要的（>总药物相关物质的 10%）循环代谢物，分别占药物相关物质的约 15%和 22%。未改变的[C]pevonedistat 分别占尿液和粪便中剂量的约 4%和 17%。在排泄物中，氧化代谢物 M1、M2 和 M3 是最丰富的药物相关成分，分别代表给予剂量的约 27%、26%和 15%。基于癌症患者的游离血浆暴露和体外 NAE 抑制，预计代谢物 M1 和 M2 对整体体内药理活性的贡献最小。在大鼠和狗（毒理学评估中使用的两种临床前物种）血浆中的暴露量高于人血浆中的暴露量，而这些代谢物的暴露量在安全和耐受剂量下更高。反应表型研究表明，CYP3A4/5 是负责 pevonedistat 代谢清除的主要酶。 意义声明：本研究详细描述了首创的 NEDD8-激活酶抑制剂 pevonedistat 在癌症患者静脉给药后的代谢和清除机制。Pevonedistat 被生物转化为两种主要的循环代谢物，在非临床毒理学物种中的暴露量高于人类。与 pevonedistat 的总体靶标药理作用相比，这些代谢物的药理活性贡献最小。肾脏清除不是未改变的 pevonedistat（约 4%的剂量）的重要排泄途径。
