Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas

Abstract

Summary Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of 14 Clenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days. The collected material was analyzed for total radioactivity, unchanged lenvatinib and selected metabolites. The safety and antitumor effect of a daily oral dose of 24 mg non-labeled lenvatinib were assessed in the extension phase of the study. Peak plasma concentrations of lenvatinib and total radioactivity were reached 1.6 and 1.4 h after administration, respectively, and their terminal phase half-lifes were 34.5 and 17.8 h, respectively. Unchanged lenvatinib systemic exposure accounted for 60 % of the total radioactivity in plasma. Peak concentrations of the analyzed metabolite were over 700-fold lower than the peak plasma concentration of lenvatinib. Ten days after the initial dose, the geometric mean (± CV) recovery of administered dose was 89 % ±10 %, with 64 % ±11 % recovered in feces and 25 % ±18 % in urine. Unchanged lenvatinib in urine and feces accounted for 2.5 % ±68 % of the administered dose, indicating a major role of metabolism in the elimination of lenvatinib. In conclusion, lenvatinib is rapidly absorbed and extensively metabolized, with subsequent excretion in urine and, more predominantly, in feces. Additionally, lenvatinib showed acceptable safety and preliminary antitumor activity.

Outcome and characteristics of patients with malignant pleural effusion from differentiated thyroid carcinoma

“…It might depend on the nature of the surgery and, perhaps more importantly, the half-life of each targeted agents. For example, the terminal elimination half-life of lenvatinib was approximately 35 hours [14]. It indicates that lenvatinib is almost washed out from the body after its cessation for 7 days (equivalent to approximately five half-lives).…”

Lenvatinib: First Global Approval

“…Plasma levels of lenvatinib decline bi-exponentially after C max is attained, with a terminal elimination half-life (t ) of *28 h [4]. In patients with solid tumours, *64 % of radioactive lenvatinib was eliminated in the faeces and *25 % in the urine [4,31].…”

Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma

“…Earlier studies have shown that lenvatinib exposure is neither affected by food intake (7) or co-administration of CYP3A4 inhibitors and inducers (8, 9). Lenvatinib is rapidly and well-absorbed; it is also extensively metabolized, with predominant excretion in feces, and to a smaller extent in urine (10). The primary objectives of this study were to identify the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and the pharmacokinetic (PK) profile of lenvatinib.…”