Karyopharm Therapeutics, 85 Wells Ave, Newton, MA, 02459, USA.
Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
Clin Pharmacokinet. 2021 Aug;60(8):957-969. doi: 10.1007/s40262-021-01016-y. Epub 2021 Apr 29.
The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis. Selinexor is a selective inhibitor of nuclear export and is an active agent in various malignancies. It is currently approved for relapsed or refractory diffuse large B-cell lymphoma as well as multiple myeloma. Following oral administration, selinexor exhibits linear and time-independent pharmacokinetics (PK) across a wide dose range, with moderately rapid absorption (time to reach maximum concentration [T] 2-4 h) and moderate elimination (half-life [t] 6-8 h). Selinexor PK observed among patients with various solid tumors and hematologic malignancies is consistent irrespective of disease. Population PK analyses demonstrated the PK of selinexor is well-described by a two-compartment model, with significant relationships for body weight on apparent clearance and apparent central volume of distribution, and sex on apparent clearance, which result in clinically non-relevant changes in exposure. These analyses also suggested selinexor PK are not significantly impacted by various concomitant medications and organ dysfunction (hepatic/renal). The time course of selinexor PK appears similar between pediatric and adult patients, although higher exposures have been observed among pediatric patients relative to adults administered similar milligrams per meter squared (mg/m) doses of selinexor.
许多肿瘤抑制蛋白 (TSP) 和癌蛋白转录 RNA 的功能在很大程度上取决于它们在细胞内的位置。Exporin 1 复合物 (XPO1) 将许多这些分子从细胞核运送到细胞质中，从而使 TSP 失活并激活癌蛋白转录 RNA。这些分子或 XPO1 的异常会增加这种易位过程，导致癌变。Selinexor 是一种核输出的选择性抑制剂，是各种恶性肿瘤的有效药物。它目前被批准用于复发性或难治性弥漫性大 B 细胞淋巴瘤以及多发性骨髓瘤。口服给予 selinexor 后，在广泛的剂量范围内表现出线性和时间独立的药代动力学 (PK)，具有适度快速的吸收 (达到最大浓度 [T] 的时间 2-4 小时) 和适度的消除 (半衰期 [t] 6-8 小时)。在患有各种实体瘤和血液恶性肿瘤的患者中观察到的 selinexor PK 是一致的，与疾病无关。群体 PK 分析表明，selinexor 的 PK 由两室模型很好地描述，体重对表观清除率和表观中央分布容积有显著关系，性别对表观清除率有显著关系，这导致暴露的临床无关变化。这些分析还表明，selinexor PK 不受各种伴随药物和器官功能障碍 (肝/肾) 的显著影响。虽然在给予类似毫克每平方米 (mg/m) 剂量的 selinexor 的儿科患者中观察到更高的暴露量，但儿科患者和成人患者之间的 selinexor PK 时间过程似乎相似。
