Metabolic disposition of [¹⁴C]-abivertinib, an epidermal growth factor receptor tyrosine kinase inhibitor: Role of glutathione conjugation

Lu Wang¹ | Lian Guo² | Yixiang Wang² | Renhua Guo³ | Zhaoqiang Xu⁴ | Zhengzhen Gao² | Lijun Xie¹ | Juan Chen¹ | Ying Chen¹ | Yun Liu¹ | Hongwen Zhang¹ | Lihua Bao³ | Wanhong Xu⁵ | Mingshe Zhu^2,6 | Feng Shao^1,7 | Yongqian Shu³

¹Phase 1 Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China; ²Department of DMPK Service, Lab Testing Division, WuXi AppTec Co. Ltd., Nanjing, China; ³Department of Oncology, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China; ⁴Department of Nuclear Medicine, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China; ⁵ACEA Pharmaceutical Research, Zhejiang, Hangzhou, China; ⁶MassDefect Technologies, Princeton, NJ, USA; ⁷Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China

Abstract

Aims: To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of [14 C]-abivertinib. Blood, urine and faeces were collected. Mass balance of radioactivity, the pharmacokinetics of abivertinib, and the total radioactivity were determined. Metabolite profiling and characterisation were performed.

Results: The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces.

Conclusion: Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

Keywords:

 EGFR-TKI; mass balance; metabolism; pharmacokinetics; radiolabelled study.