Attwa Mohamed W, AlRabiah Haitham, Abdelhameed Ali S, Kadi Adnan A
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Front Chem. 2024 Sep 26;12:1323738. doi: 10.3389/fchem.2024.1323738. eCollection 2024.
CEP-37440 was synthesized and supplied by the research and development division of Teva Branded Pharmaceutical Products (West Chester, PA, United States). CEP-37440 represents a newly developed compound that exhibits selectivity inhibition of Focal Adhesion Kinase and Anaplastic Lymphoma Kinase FAK/ALK receptors, demonstrating novel characteristics as an orally active inhibitor. The simultaneous inhibition of ALK and FAK can effectively address resistance and enhance the therapeutic efficacy against tumors through a synergistic mechanism.
The objective of this research was to create an LC-MS/MS method that is precise, efficient, environmentally friendly, and possesses a high level of sensitivity for the quantification of CEP-37440 in human liver microsomes (HLMs). The aforementioned approach was subsequently employed to evaluate the metabolic stability of CEP-37440 in HLMs in an in vitro setting. The validation procedures for the LC-MS/MS analytical method in the HLMs were performed following the bio-analytical method validation guidelines set out by the US-FDA. The AGREE program was utilized to assess the ecological impacts of the current LC-MS/MS methodology.
The calibration curve linearity was seen in the range of 1-3000 ng/mL. The inter-day accuracy (% RE) exhibited a range of -2.33% to 3.22%, whilst the intra-day accuracy demonstrated a range of -4.33% to 1.39%. The inter-day precision (% RSD) exhibited a range of 0.38% to 3.60%, whilst the intra-day precision demonstrated a range of 0.16% to 6.28%. The determination of the in vitro half-life (t) and moderate intrinsic clearance (C) of CEP-37440 yielded values of 23.24 min and 34.74 mL/min/kg, respectively. The current manuscript is considered the first analytical study for CEP-37440 quantification with the application to metabolic stability assessment. These results suggest that CEP-37440 can be categorized as a pharmaceutical agent with a moderate extraction ratio. Consequently, it is postulated that the administration of CEP-37440 to patients may not lead to the accrual of dosages within the human organs. According to P450 metabolic and DEREK software, minor structural alterations to the ethanolamine moiety or substitution of the group in drug design have the potential to enhance the metabolic stability and safety profile of novel derivatives in comparison to CEP-37440.
CEP - 37440由梯瓦品牌制药产品公司（美国宾夕法尼亚州韦斯特切斯特）的研发部门合成并提供。CEP - 37440是一种新开发的化合物，对粘着斑激酶和间变性淋巴瘤激酶FAK/ALK受体具有选择性抑制作用，展现出作为口服活性抑制剂的新特性。同时抑制ALK和FAK可有效解决耐药性问题，并通过协同机制提高抗肿瘤治疗效果。
本研究的目的是建立一种用于定量测定人肝微粒体（HLMs）中CEP - 37440的液相色谱 - 串联质谱（LC - MS/MS）方法，该方法要精确、高效、环保且具有高灵敏度。随后采用上述方法在体外评估CEP - 37440在HLMs中的代谢稳定性。HLMs中LC - MS/MS分析方法的验证程序按照美国食品药品监督管理局（US - FDA）制定的生物分析方法验证指南进行。利用AGREE程序评估当前LC - MS/MS方法的生态影响。
校准曲线在1 - 3000 ng/mL范围内呈线性。日间准确度（%RE）范围为 - 2.33%至3.22%，而日内准确度范围为 - 4.33%至1.39%。日间精密度（%RSD）范围为0.38%至3.60%，而日内精密度范围为0.16%至6.28%。CEP - 37440的体外半衰期（t）和中度内在清除率（C）测定值分别为23.24分钟和34.74 mL/min/kg。本手稿被认为是首次对CEP - 37440进行定量分析并应用于代谢稳定性评估的研究。这些结果表明，CEP - 37440可归类为提取率适中的药物制剂。因此，推测给患者使用CEP - 37440可能不会导致人体器官内药物剂量的累积。根据P450代谢和DEREK软件，与CEP - 37440相比，在药物设计中对乙醇胺部分进行微小结构改变或基团取代有可能提高新型衍生物的代谢稳定性和安全性。
