Absorption, distribution, metabolism, and excretion of [¹⁴C]SH-1028, a third-generation EGFR-TKI, in rats and humans

SH-1028 is an irreversible third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) developed for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. This study aimed to systematically investigate the absorption, distribution, metabolism and excretion (ADME) profiles of SH-1028 in rats and humans using a [¹⁴C] radiolabeled tracer.

This integrated preclinical and clinical investigation comprised a radiolabeled mass balance study with quantitative whole-body autoradiography (QWBA) in rats, followed by a human mass balance study of [¹⁴C]SH-1028. Blood, urine and fecal samples were collected at predefined time points or intervals. Plasma pharmacokinetics, mass balance, metabolite profiling, and structural identification of major metabolites were assessed. Safety was also evaluated throughout the clinical phase.

Following a single oral dose of [¹⁴C]SH-1028 in humans, the mean total recovery of radioactivity was 85.02%, with 81.55% in feces and 3.48% in urine, indicating fecal excretion as the primary elimination pathway, which is consistent with observations in rats. Two major circulating metabolites not detected in animal studies, M541i and Imp2, were identified in human plasma, accounting for 20% and 60% of the total plasma radioactivity, respectively. The cumulative excretion of unchanged SH-1028 in urine and feces accounted for only 3.52% of the administered dose, indicating that SH-1028 undergoes extensive metabolism in vivo and is eliminated primarily as metabolites.

SH-1028 was well tolerated in subjects after a single oral administration of 200 mg containing 3.26 MBq (88 μCi) of [¹⁴C]SH-1028. The parent drug and its metabolites M541i and Imp2 were identified as the major circulating components. Mass balance studies in both rats and humans consistently demonstrated that SH-1028 is eliminated predominantly via fecal excretion, undergoes extensive metabolism, and is cleared primarily as metabolites.