Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Room G27e 5117 Centre Ave, Pittsburgh, PA, 15213, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Chemother Pharmacol. 2024 Aug;94(2):271-283. doi: 10.1007/s00280-024-04675-3. Epub 2024 May 14.
The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is an apical initiator of DNA damage response pathways. Several ATR inhibitors (ATRi) are in clinical development including berzosertib (formerly M6620, VX-970). Although clinical studies have examined plasma pharmacokinetics (PK) in humans, little is known regarding dose/exposure relationships and tissue distribution. To understand these concepts, we extensively characterized the PK of berzosertib in mouse plasma and tissues.
A highly sensitive LC-MS/MS method was utilized to quantitate berzosertib in plasma and tissues. Dose proportionality was assessed in female BALB/c mice following single IV doses (2, 6, 20 or 60 mg/kg). A more extensive PK study was conducted in tumor-bearing mice following a single IV dose of 20 mg/kg to evaluate distribution to tissues. PK parameters were calculated by non-compartmental analysis (NCA). A compartmental model was developed to describe the PK behavior of berzosertib. Plasma protein binding was determined in vitro.
Increased doses of berzosertib were associated with less than proportional increases in early plasma concentrations and greater than proportional increase in tissue exposure, attributable to saturation of plasma protein binding. Berzosertib extensively distributed into bone marrow, tumor, thymus, and lymph nodes, however; brain and spinal cord exposure was less than plasma.
The nonlinear PK of berzosertib displayed here can be attributed to saturation of plasma protein binding and occurred at concentrations close to those observed in clinical trials. Our results will help to understand preclinical pharmacodynamic and toxicity data and to inform optimal dosing and deployment of berzosertib.
共济失调毛细血管扩张症和 Rad3 相关（ATR）蛋白复合物是 DNA 损伤反应途径的顶端起始因子。几种 ATR 抑制剂（ATRi）正在临床开发中，包括 berzosertib（前体 M6620，VX-970）。虽然临床研究已经在人体中检查了血浆药代动力学（PK），但对于剂量/暴露关系和组织分布知之甚少。为了了解这些概念，我们广泛描述了 berzosertib 在小鼠血浆和组织中的 PK。
使用高度敏感的 LC-MS/MS 方法定量检测血浆和组织中的 berzosertib。在雌性 BALB/c 小鼠中，在单次 IV 剂量（2、6、20 或 60mg/kg）后评估剂量比例。在荷瘤小鼠中进行了更广泛的 PK 研究，在单次 IV 剂量 20mg/kg 后评估了组织分布。通过非房室分析（NCA）计算 PK 参数。开发了一个房室模型来描述 berzosertib 的 PK 行为。体外测定了血浆蛋白结合。
berzosertib 的剂量增加与早期血浆浓度的不成比例增加和组织暴露的不成比例增加相关，这归因于血浆蛋白结合的饱和。berzosertib 广泛分布于骨髓、肿瘤、胸腺和淋巴结，但脑和脊髓的暴露量低于血浆。
这里显示的 berzosertib 的非线性 PK 可归因于血浆蛋白结合的饱和，并且发生在接近临床试验中观察到的浓度。我们的结果将有助于了解临床前药效学和毒性数据，并为最佳剂量和 berzosertib 的部署提供信息。
