Peposertib 是一种口服 DNA 依赖性蛋白激酶抑制剂。我们评估了食物对其药代动力学的影响，并在 I 期、开放标签、三期交叉研究 (NCT04702698) 中检查了崩解片口服混悬液 (OS) 的药代动力学。十二名健康志愿者被随机分配接受六种治疗序列之一。他们在禁食或进食条件下接受单剂量peposertib 100mg作为薄膜包衣片剂（“禁食片剂”或“片剂喂养”）或在禁食条件下作为OS（“OS禁食”），在治疗之间进行冲洗。使用健康志愿者是可能的，因为尽管 peposertib 的作用机制是抑制 DNA 修复，但它在动物中没有表现出遗传毒性作用。 Peposertib 片剂观察到轻微的食物效应。进食与空腹比率为：从时间 0 到时间 t 的曲线下面积 (AUC0-t)，123.81%（90% 置信区间 [CI]：108.04，141.87%）； AUC从零到无穷大（AUC0-∞），110.28%（90% CI 100.71，120.77%）；最大浓度 (Cmax) 104.47% (90% CI: 79.15, 137.90%)。在进食条件下，Cmax 延迟（达到最大浓度的中位时间 [Tmax] 为 3.5 小时 [片剂喂食] vs. 1 小时 [片剂禁食]）。 OS 与片剂（空腹）比率为：AUC0-t，124.83%（90% CI：111.50%，139.76%）； AUC0-∞, 119.05% (90% CI: 104.47, 135.67%); Cmax 173.29%（90% CI：135.78，221.16%）。中位 Tmax 为 0.5 小时（OS 禁食），而中位 Tmax 为 1 小时（片剂）。所有治疗方法在健康志愿者中均具有良好的耐受性。 Peposertib 片剂可与食物同服或单独服用；如果与化疗或放疗联合使用，必须考虑延迟 Cmax 以优化化疗或放疗增敏作用。 peposertib OS 形式代表了患有导致吞咽困难的特定癌症患者的另一种给药途径。然而，OS 形式应该成为相关环境中未来剂量优化策略的一部分。© 2023 Merck KGaA 和 Nuvisan GmbH。 《临床和转化科学》由 Wiley periodicals LLC 代表美国临床药理学和治疗学会出版。

Peposertib is an orally administered inhibitor of DNA-dependent protein kinase. We evaluated the effect of food on its pharmacokinetics, and examined the pharmacokinetics of an oral suspension (OS) of disintegrated tablets, in a phase I, open-label, crossover three-period study (NCT04702698). Twelve healthy volunteers were randomized to one of six treatment sequences. They received a single dose of peposertib 100 mg as film-coated tablets under fasted or fed conditions ("tablet fasted" or "tablet fed") or as an OS under fasted conditions ("OS fasted"), with washout between treatments. Using healthy volunteers was possible because, despite its mechanism of action being suppression of DNA repair, peposertib has shown no genotoxic effect in animals. A mild food effect was observed with peposertib tablets. Fed-to-fasted ratios were: area under the curve from time 0 to time t (AUC0-t ), 123.81% (90% confidence interval [CI]: 108.04, 141.87%); AUC from zero to infinity (AUC0-∞ ), 110.28% (90% CI 100.71, 120.77%); and maximum concentration (Cmax ) 104.47% (90% CI: 79.15, 137.90%). Cmax was delayed under fed conditions (median time to maximum concentration [Tmax ] was 3.5 h [tablet fed] vs. 1 h [tablet fasted]). OS-to-tablet (fasted) ratios were: AUC0-t , 124.83% (90% CI: 111.50%, 139.76%); AUC0-∞ , 119.05% (90% CI: 104.47, 135.67%); and Cmax 173.29% (90% CI: 135.78, 221.16%). Median Tmax was 0.5 h (OS fasted) versus 1 h (tablet). All treatments were well-tolerated in healthy volunteers. Peposertib tablets can be taken with or without food; if combined with chemotherapy or radiotherapy, the delay in Cmax must be considered to optimize the chemo- or radiosensitizing effect. The peposertib OS form represents an alternative route of administration in patients with specific cancers causing dysphagia. However, the OS form should be part of future dose optimization strategies in relevant settings.© 2023 Merck KGaA and Nuvisan GmbH. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.