A phase I study investigating the absorption, metabolism, and excretion of [14C] anlotinib in patients with advanced refractory solid tumors.

Abstract

e14701 Background: 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, and has shown antitumor activity in patients with advanced refractory solid tumors. The human plasma pharmacokinetics of anlotinib have been described previously, but detailed analyses of the absorption, metabolism and excretion pathways of anlotinib have not yet been published. Methods: Six male patients were divided into two groups, one group included two patients was performed by 13.51mg Anlotinib hydrochloride and 0.64 mg/80 μCi [14C] anlotinib hydrochloride and the rest four patients in another group received 13.19mg anlotinib hydrochloride and 0.96mg/120 μCi [14C] anlotinib hydrochloride, followed by collection of blood, urine, and fecal samples. The primary outcomes of study were absorption, metabolism, and excretion of [14C] anlotinib and the second outcomes were efficacy and safety. Results: In plasma, the average time of total plasma radioactivity peak (Tmax) was 4.42h and the average peak concentration (Cmax) was 18.80 ng Eq./g. The average value of AUC last was 4071 h∙ng Eq./g, AUC0-∞ was 13555 h∙ng Eq./g, and MRT0-t was 145h. The average recovery rate of total radioactivity in urine and feces was 62.03%. Prototype drugs and metabolites were mainly excreted through feces, accounting for 48.52% of the administered dose, otherwise rine excretion accounted for 13.51%. The liver and kidney were the main drug excretion organs. Five patients developed adverse reactions, and one person developed SAE. Three of study population were assessed as stable disease (SD), two with partial response (PR), and one had progressive disease (PD). Conclusions: Anlotinib showed a favourable pharmacokinetic profile with high absolute bioavailability and an extensive hepatic metabolism. The adverse events and efficacy were as expected. Clinical trial information: CTR20160329.