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

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 mu Ci oral suspension of [C-14]-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.

Automated summary

The study found that in patients with advanced non-small cell lung cancer, abivertinib is primarily eliminated via the faecal route, and unchanged abivertinib plays a key role in the clearance and metabolism process in the body.