Attwa Mohamed W, Abdelhameed Ali S, Kadi Adnan A
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Heliyon. 2024 Jul 5;10(13):e34109. doi: 10.1016/j.heliyon.2024.e34109. eCollection 2024 Jul 15.
The orally given, irreversible, third-generation inhibitor of the epidermal growth factor receptor (EGFR), known as Nazartinib (EGF816), is now undergoing investigation in Phase II clinical trials conducted by Novartis for Non-Small Cell Lung Cancer. The primary aim of the current research was to establish a rapid, specific, environmentally friendly, and highly versatile UPLC-MS/MS methodology for the determination of nazartinib (NZT) levels in human liver microsomes (HLMs). Subsequently, same approach was used to examine the metabolic stability of NZT. The UPLC-MS/MS method employed in HLMs was validated as stated in the bioanalytical method validation criteria outlined by the US- FDA. The evaluation of the metabolic stability of NZT and the identification of potentially structural alarms were performed using the StarDrop software package that includes the P450 and DEREK software. The calibration curve for NZT showed a linearity in the range from 1 to 3000 ng/mL. The inter-day accuracy and precision exhibited a range of values between -4.33 % and 4.43 %, whereas the intra-day accuracy and precision shown a range of values between -2.78 % and 7.10 %. The sensitivity of the developed approach was verified through the determination of a LLOQ of 0.39 ng/mL. The intrinsic clearance and in vitro half-life of NZT were assessed to be 46.48 mL/min/kg and 17.44 min, respectively. In our preceding inquiry, we have effectively discerned the bioactivation center, denoted by the carbon atom between the unsaturated conjugated system and aliphatic linear tertiary amine. In the context of computational software, making minor adjustments or substituting the dimethylamino-butenoyl moiety throughout the drug design process may increase the metabolic stability and safety properties of new synthesized derivatives. The efficiency of utilizing different in silico software approaches to conserve resources and reduce effort was proved by the outcomes attained from in vitro incubation experiments and the use of NZT in silico software.
口服给药的不可逆第三代表皮生长因子受体（EGFR）抑制剂纳扎替尼（EGF816），目前正在诺华公司开展的用于非小细胞肺癌的II期临床试验中接受研究。当前研究的主要目的是建立一种快速、特异、环境友好且高度通用的超高效液相色谱-串联质谱（UPLC-MS/MS）方法，用于测定人肝微粒体（HLM）中纳扎替尼（NZT）的水平。随后，采用相同方法检测NZT的代谢稳定性。在HLM中使用的UPLC-MS/MS方法按照美国食品药品监督管理局（US-FDA）概述的生物分析方法验证标准进行了验证。使用包含P450和DEREK软件的StarDrop软件包对NZT的代谢稳定性进行评估，并识别潜在的结构警示。NZT的校准曲线在1至3000 ng/mL范围内呈线性。日间准确度和精密度的值在-4.33%至4.43%之间，而日内准确度和精密度的值在-2.78%至7.10%之间。通过测定0.39 ng/mL的定量下限（LLOQ）验证了所开发方法的灵敏度。NZT的内在清除率和体外半衰期分别评估为46.48 mL/min/kg和17.44分钟。在我们之前的研究中，我们有效地识别了生物活化中心，该中心由不饱和共轭体系与脂肪族直链叔胺之间的碳原子表示。在计算软件的背景下，在整个药物设计过程中对二甲基氨基丁烯酰部分进行微调或替换，可能会提高新合成衍生物的代谢稳定性和安全性。体外孵育实验以及在计算机软件中使用NZT所获得的结果证明了利用不同计算机软件方法来节省资源和减少工作量的效率。
