Mitra Amitava, Ahsan Julie Mackey, Tabachri Marilyn, El-Shahat Taha, Leoni Mollie, Dale Stephen
Clinical Pharmacology, Kura Oncology, Inc., San Diego, California, USA.
Clinical Development, Kura Oncology, Inc., San Diego, California, USA.
Clin Transl Sci. 2025 Feb;18(2):e70153. doi: 10.1111/cts.70153.
Ziftomenib, a potent, selective inhibitor that binds menin at the lysine methyltransferase 2 interaction site, has demonstrated promising clinical activity with manageable toxicity in heavily pretreated patients with acute myeloid leukemia (AML) and nucleophosmin 1 mutations. This phase 1, open-label study characterized the absorption, metabolism, excretion, and bioavailability of ziftomenib in healthy men and comprised two parts. In part A, a single oral dose of ziftomenib 400 mg (containing 250 μCi [C]-ziftomenib) was given to evaluate routes and rates of elimination, total radioactivity, and other pharmacokinetic parameters. In part B, a single oral dose of ziftomenib 400 mg followed by an intravenous dose of ziftomenib < 100 μg (containing 1 μCi [C]-ziftomenib) was administered to evaluate absolute bioavailability (both n = 8 patients). A median t of 3.5 h and an elimination t of 61.5 h demonstrated rapid ziftomenib absorption and enabled once-daily dosing. Total radioactivity recovery was 89.7% in feces and 0.5% in urine over 480 h. Absolute bioavailability of 12.9% was observed. Ziftomenib was primarily metabolized by oxidation, N-demethylation, and N-dealkylation, with 19 metabolites recovered in plasma. All metabolites were considered minor (< 10% of total drug-related exposure). Ziftomenib was the most abundant plasma component (> 10% of total drug-related exposure). In conclusion, ziftomenib underwent limited metabolism following absorption and was primarily excreted as unchanged parent drug in feces. Ziftomenib was well tolerated with no new safety concerns in healthy men. Considering the pharmacokinetic profile and manageable safety outcomes, these findings support further clinical investigation of ziftomenib as treatment for AML.
齐弗托米尼布是一种强效、选择性抑制剂，可在赖氨酸甲基转移酶2相互作用位点与Menin结合，在预处理严重的急性髓系白血病（AML）和核磷蛋白1突变患者中已显示出有前景的临床活性且毒性可控。这项1期开放标签研究对健康男性体内齐弗托米尼布的吸收、代谢、排泄和生物利用度进行了表征，包括两个部分。在A部分，给予单次口服400毫克齐弗托米尼布（含250微居里[C] - 齐弗托米尼布），以评估消除途径和速率、总放射性及其他药代动力学参数。在B部分，先给予单次口服400毫克齐弗托米尼布，随后静脉注射<100微克齐弗托米尼布（含1微居里[C] - 齐弗托米尼布），以评估绝对生物利用度（两组均为n = 8例患者）。中位达峰时间为3.5小时，消除半衰期为61.5小时，表明齐弗托米尼布吸收迅速，可每日给药一次。在480小时内，粪便中总放射性回收率为89.7%，尿液中为0.5%。观察到绝对生物利用度为12.9%。齐弗托米尼布主要通过氧化、N - 去甲基化和N - 脱烷基化代谢，血浆中回收了19种代谢物。所有代谢物均被视为次要成分（<总药物相关暴露的10%）。齐弗托米尼布是血浆中最丰富的成分（>总药物相关暴露的10%）。总之，齐弗托米尼布吸收后代谢有限，主要以未改变的母体药物形式经粪便排泄。在健康男性中，齐弗托米尼布耐受性良好，无新的安全问题。考虑到药代动力学特征和可控的安全性结果，这些发现支持进一步对齐弗托米尼布作为AML治疗药物进行临床研究。
