Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Molecules. 2023 Oct 23;28(20):7220. doi: 10.3390/molecules28207220.
Acalabrutinib, commercially known as Calquence, is a pharmacological molecule that has robust inhibitory activity against Bruton tyrosine kinase. The medicine in question was carefully developed by the esteemed pharmaceutical company AstraZeneca. The FDA granted authorization on 21 November 2019 for the utilization of acalabrutinib (ACB) in the treatment of small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL) in adult patients. The aim of this study was to develop a UPLC-MS/MS method that is effective, accurate, environmentally sustainable, and has a high degree of sensitivity. The methodology was specifically developed with the intention of quantifying ACB in human liver microsomes (HLMs). The methodology described above was subsequently utilized to assess the metabolic stability of ACB in HLMs in an in vitro environment. The validation procedures for the UPLC-MS/MS method in the HLMs were conducted in accordance with the bioanalytical method validation criteria established by the U.S.- DA. The utilization of the StarDrop software (version 6.6), which integrates the P450 metabolic module and DEREK software (KB 2018 1.1), was employed for the purpose of evaluating the metabolic stability and identifying potential hazardous alarms associated with the chemical structure of ACB. The calibration curve, as established by the ACB, demonstrated a linear correlation across the concentration range of 1 to 3000 ng/mL in the matrix of HLMs. The present study conducted an assessment of the accuracy and precision of the UPLC-MS/MS method in quantifying inter-day and intra-day fluctuations. The inter-day accuracy demonstrated a spectrum of values ranging from -1.00% to 8.36%, whilst the intra-day accuracy presented a range of values spanning from -2.87% to 4.11%. The t and intrinsic clearance (Cl) of ACB were determined through in vitro testing to be 20.45 min and 39.65 mL/min/kg, respectively. The analysis concluded that the extraction ratio of ACB demonstrated a moderate level, thus supporting the recommended dosage of ACB (100 mg) to be administered twice daily for the therapeutic treatment of persons suffering from B-cell malignancies. Several computational tools have suggested that introducing minor structural alterations to the butynoyl group, particularly the alpha, beta-unsaturated amide moiety, or substituting this group during the drug design procedure, could potentially enhance the metabolic stability and safety properties of novel derivatives in comparison to ACB.
阿卡替尼，商品名为 Calquence，是一种药理学分子，对布鲁顿酪氨酸激酶具有强大的抑制活性。这种备受赞誉的制药公司阿斯利康（AstraZeneca）精心开发了这种药物。美国食品和药物管理局（FDA）于 2019 年 11 月 21 日批准将阿卡替尼（ACB）用于治疗成人小淋巴细胞淋巴瘤（SLL）或慢性淋巴细胞白血病（CLL）。本研究旨在开发一种有效、准确、环境可持续且具有高灵敏度的 UPLC-MS/MS 方法。该方法是专门为定量人肝微粒体（HLMs）中的 ACB 而开发的。上述方法随后用于评估 ACB 在 HLMs 中的体外代谢稳定性。HLMs 中的 UPLC-MS/MS 方法的验证程序是根据美国 FDA 制定的生物分析方法验证标准进行的。使用 StarDrop 软件（版本 6.6），该软件集成了 P450 代谢模块和 DEREK 软件（KB 2018 1.1），用于评估 ACB 的化学结构的代谢稳定性和识别潜在的危险警报。ACB 建立的校准曲线在 HLMs 基质中的浓度范围为 1 至 3000ng/mL 时呈线性相关。本研究评估了 UPLC-MS/MS 方法在定量日内和日间波动方面的准确性和精密度。日内准确度的范围为-1.00%至 8.36%，而日间准确度的范围为-2.87%至 4.11%。通过体外试验测定，ACB 的 t 和内在清除率（Cl）分别为 20.45 分钟和 39.65mL/min/kg。分析表明，ACB 的提取率为中等水平，因此支持推荐剂量的 ACB（100mg）每天两次用于治疗 B 细胞恶性肿瘤患者。几种计算工具表明，在药物设计过程中对丁炔酰基进行微小的结构改变，特别是对α，β-不饱和酰胺部分进行改变，或者用其他基团替代该基团，可能会提高新型衍生物的代谢稳定性和安全性，与 ACB 相比有所提高。
