Cancer Therapeutics Program, UPMC Hillman Cancer Center, 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. 2022 Jun;89(6):795-807. doi: 10.1007/s00280-022-04436-0. Epub 2022 May 4.
Ataxia Telangiectasia and Rad3-related (ATR) is a pivotal component of the DNA damage response and repair pathways that is activated in responses to cytotoxic cancer treatments. Several ATR inhibitors (ATRi) are in development that block the ATR mediated DNA repair and enhance the damage associated with cytotoxic therapy. BAY-1895344 (elimusertib) is an orally available ATRi with preclinical efficacy that is in clinical development. Little is known about the pharmacokinetics (PK) which is of interest, because tissue exposure and ATR inhibition may relate to toxicities or responses.
To evaluate BAY-1895344 PK, a sensitive LC-MS/MS method was utilized for quantitation in mouse plasma and tissues. PK studies in mice were first conducted to determine dose linearity. In vivo metabolites were identified and analyzed semi-quantitatively. A compartmental PK model was developed to describe PK behavior. An extensive PK study was then conducted in tumor-bearing mice to quantitate tissue distribution for relevant tissues.
Dose linearity was observed from 1 to 10 mg/kg PO, while at 40 mg/kg PO bioavailability increased approximately fourfold due to saturation of first-pass metabolism, as suggested by metabolite analyses and a developed compartmental model. Longer half-lives in PO treated mice compared to IV treated mice indicated absorption-rate limited elimination. Tissue distribution varied but showed extensive distribution to bone marrow, brain, and spinal cord.
Complex PK behavior was limited to absorption processes which may not be recapitulated clinically. Tissue partition coefficients may be used to contrast ATR inhibitors with respect to their efficacy and toxicity.
共济失调毛细血管扩张症突变基因与 Rad3 相关蛋白（ATR）是细胞毒性癌症治疗反应中 DNA 损伤反应和修复途径的关键组成部分。目前正在开发几种 ATR 抑制剂（ATRi），这些抑制剂可阻断 ATR 介导的 DNA 修复，并增强与细胞毒性治疗相关的损伤。BAY-1895344（elimusertib）是一种具有临床前疗效的口服 ATRi，目前正在临床开发中。由于组织暴露和 ATR 抑制可能与毒性或反应有关，因此对其药代动力学（PK）知之甚少。
为了评估 BAY-1895344 的 PK，我们使用灵敏的 LC-MS/MS 方法对小鼠血浆和组织中的药物进行定量。首先在小鼠中进行 PK 研究以确定剂量线性关系。鉴定并分析体内代谢物进行半定量分析。建立了一个房室 PK 模型来描述 PK 行为。然后在荷瘤小鼠中进行了广泛的 PK 研究，以定量相关组织的组织分布。
口服 1 至 10 mg/kg 时观察到剂量线性关系，而口服 40 mg/kg 时，由于首过代谢饱和，生物利用度增加了约四倍，这可通过代谢物分析和开发的房室模型得到证实。与 IV 治疗小鼠相比，PO 治疗小鼠的半衰期更长，这表明吸收速率限制了消除。组织分布不同，但骨髓、脑和脊髓广泛分布。
复杂的 PK 行为仅限于吸收过程，这在临床上可能无法重现。组织分配系数可用于比较 ATR 抑制剂的疗效和毒性。
