A phase I study investigation of metabolism, and disposition of [(14)C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

PURPOSE: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. METHODS: Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [(14)C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [(14)C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [(14)C]-anlotinib were collected. The absorption, metabolism, and excretion of [(14)C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. RESULTS: In plasma, the average time to peak concentration (T(max)) of total radioactivity was 4.42 h and the average peak concentration (C(max)) of total radioactivity was 18.80 ng Eq./g. The average values of AUC(0-last), AUC(0-∞), and MRT(0-t) were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. CONCLUSIONS: Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00280-020-04062-8) contains supplementary material, which is available to authorized users.