In this article, we will discuss Lenvatinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Lenvatinib is a kinase inhibitor that inhibits the kinase activities of vascular endothelial
growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4).
Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis,
tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone.
In patients with solid tumors administered single and multiple doses of LENVIMA once
daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 mg (0.1 times the recommended clinical dose of 24 mg) to 32 mg (1.33 times the recommended clinical dose of 24 mg) with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose.
Administration with a high fat meal (approximately 900 calories of which approximately 55% were from fat, 15% from protein, and 30% from carbohydrates) did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.
In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% at
concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59 to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.
The terminal elimination half-life of lenvatinib was approximately 28 hours.
The main metabolic pathways for lenvatinib in humans were identified as enzymatic
(CYP3A and aldehyde oxidase) and non-enzymatic processes.
Ten days after a single administration of radiolabeled lenvatinib, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively