Zhou Chen, Xie Lijun, Liu Wei, Zhang Lingling, Zhou Sufeng, Wang Lu, Chen Juan, Li Huan, Zhao Yuqing, Zhu Bei, Ding Sijia, Zhang Chen, Shao Feng
Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Nuclear Medicine Department, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Ann Transl Med. 2021 May;9(10):867. doi: 10.21037/atm-21-1606.
Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants.
Total radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration.
The safety and tolerability of a single oral dose of 110 mg/50 µCi [C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a T of 4.0 h; however, TRA was cleared slowly , with a mean terminal elimination phase (half-life, T) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively.
Almonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized before excretion and is excreted as a parent drug and metabolites mainly via feces.
The trial registration number: CTR20192291.
甲磺酸阿美替尼片（HS-10296，江苏豪森药业集团有限公司，中国上海）是一种新型的选择性第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）。一项关于阿美替尼在非小细胞肺癌（NSCLC）患者中的I期研究显示出线性代谢趋势、良好的耐受性/安全性以及初步的抗肿瘤活性。然而，阿美替尼的代谢、排泄和物质平衡尚未明确确定。在此，我们研究了健康中国男性受试者单次口服剂量（110 mg/50 μCi）阿美替尼后的药代动力学特征和安全性。
利用液体闪烁计数器测量全血、血浆、尿液和粪便中的总放射性（TRA），以获得阿美替尼的物质平衡数据。在WinNonlin软件（Pharsight公司）中采用非房室分析方法分析全血和血浆中[C]阿美替尼及母体药物阿美替尼的药代动力学参数。通过高效液相色谱（HPLC）结合在线或离线同位素检测器分析血浆、尿液和粪便中的主要代谢产物。给药后评估药物的安全性。
单次口服110 mg/50 μCi [C]阿美替尼混悬液在健康中国男性受试者中安全性和耐受性良好。未出现明显异常或特殊不良反应。TRA在血浆中迅速达到峰值，达峰时间（T）为4.0小时；然而，TRA清除缓慢，平均终末消除相（半衰期，T）长达863小时。除母体药物外，共分析了血液、尿液和粪便中的26种代谢产物。在血浆中，母体药物是主要的药物相关成分，占TRA的69.97%，M440（阿美替尼-M2去甲基产物）是主要代谢产物，占TRA的5.08%；在尿液中，母体药物占给药剂量的0.48%，HAS-719是主要代谢产物，占给药剂量的1.20%；在粪便中，母体药物约占给药剂量的8.61%，HAS-719是主要代谢产物，占给药剂量的12.33%，其次是M541a/M470a和M617/M575，分别占给药剂量的11.8%和6.76%。
阿美替尼具有良好的安全性，母体药物是其主要的循环成分。阿美替尼在排泄前被广泛代谢，主要以母体药物和代谢产物的形式通过粪便排泄。
试验注册号：CTR20192291。
