Mechanism of Action

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor  (VEGF) receptors, VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs, including fibroblast growth factor receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT and RET.

Lenvatinib inhibited the receptor tyrosine kinases FGFR1-3, PDGFRβ and KIT (IC₅₀ <100 nM), and FLT1, FLT4, KDR and RET (IC₅₀ <10 nM). Lenvatinib showed weak activity against EGFR (IC₅₀ = 620-6500 nM).

No significant binding (>50% inhibition) to any receptor of the observed at 10 μM except for 5-HT1B and human NE transporter.

In Vitro Efficacy

Inhibition of Lenvatinib on HUVECs:

●    Inhibition of KDR phosphorylation: IC₅₀ = 0.25 nM.

●    Anti-proliferation: IC₅₀ = 3.4 nM.

●    Anti-angiogenic activity: IC₅₀ = 2.1 nM.

Anti-proliferation assay:

●    Human non-small cell lung cancer (NSCLC) H460: IC₅₀ = 14000 nM.

●    Human colorectal adenocarcinoma Colo205: IC₅₀ = 26000 nM.

In Vivo Efficacy

Xenograft model: Significant inhibition of tumor growth in human thyroid carcinoma xenograft models.

●    In papillary K1 model: 30 mg/kg/day on day 14.

●    In medullary TT model: 10 mg/kg/day on day 28.

●    SW579, thyroid-derived squamous cell carcinoma: 3 mg/kg/day on day 14.

●    8305C, a human anaplastic thyroid cancer cell line: 3 mg/kg/day on day 14.

●    RO82-W-1, follicular thyroid carcinoma: 1 mg/kg/day on day 21.

Human hepatocellular PLC/PRF/5 xenograft model: Significant inhibition dose was 3 mg/kg/day, QD on day 14.

Human NSCLC H460 xenograft model: Significant dose of tumor inhibition was 1 mg/kg/day, QD on day 14.

Human colorectal adenocarcinoma colo205 xenograft model: Significant inhibition dose was 1 mg/kg/day, QD on day 11.

Absorption of Lenvatinib

Exhibited a linear pharmacokinetics in solid tumor patients following oral dosing. The increases in C_max and AUC_inf appeared to be dose-proportional in the dose range of 0.5 to 20 mg lenvatinib.

Had a high oral bioavailability in mice (64.4%), rats (68.7%), dogs (70.4%) and monkeys (78.4%).

Was absorbed rapidly (T_max = 0.5-1 h) in rats and mice, moderate in dogs (T_max = 2 h), monkeys (T_max = 2 h) and humans (T_max = 1-5 h).

Showed a half-life of 19-46.5 h in humans, much longer than those in mice (1.74-2.09 h), rats (3.61-5.27 h), dogs (4.76 h) and monkeys (4.07 h) after oral administration.

Had a low clearance in mice (345 mL/h/kg), rats (100 mL/h/kg), dogs (368 mL/h/kg) and monkeys (238 mL/h/kg), compared to the liver blood flow, after intravenous administration. The CL/F in humans was 3.7-7.2 L/h after oral administration.

Exhibited a low tissue distribution in rats, moderate in mice and monkeys, high in dogs with the apparent volume of distribution at 392, 714, 794 and 1610 mL/kg, respectively, after intravenous administration. The volume of distribution of lenvatinib in humans was 136-312 L.

Showed a high permeability, with a Papp_(A→B) of 39.7 × 10^-6 cm/s in LLC-PK1 cell monolayer model.

Distribution of Lenvatinib

Exhibited high plasma protein binding in humans (97.9%-98.6%), rats (97.7%-98.2%), mice (96.3%-96.9%), monkeys (95.9%-96.2%) and dogs (89.7% to 91.8%).

Had a C_b:C_p ratio of 0.589-0.608 in humans, suggesting minor penetration into red blood cells. Note that lenvatinib was mainly bound to albumin in humans.

In SD rats following a single oral administration of 3 mg/kg [¹⁴C]lenvatinib mesilate:

●    The drug was widely distributed into most tissues including central nervous system, with the exposure of lenvatinib in the brain as ~2-14% of that in plasma.

●    The radioactivity reached its maximum levels in most tissues at 30 min post-dose. Relatively higher drug concentration levels were observed in liver, adrenal gland, stomach, and small intestine, compared to other organs.

●    Radioactivity concentrations decreased below the lower limit of quantification in most tissues at 168 h post-dose.

In Cynomolgus monkeys following a single oral administration of 3 mg/kg [¹⁴C]BC-lenvatinib mesilate:

●    The radioactivity of [¹⁴C]lenvatinib reached its maximum levels in most tissues at 4 h post-dose. Relatively higher drug concentration levels were observed in bile in gall bladder, urine in bladder, gall bladder, liver, choroid, ciliary body, and renal cortex, compared to other organs.

●    The radioactivity of [¹⁴C]CB lenvatinib reached its maximum levels in most tissues at 2 h post-dose. Relatively higher drug concentration levels were observed in bile in gall bladder, choroid and liver, compared to other organs. The exposure of lenvatinib in the central nervous system was 0.07 times or lower than that in the plasma.

Metabolism of Lenvatinib

Overall, the parent drug represented the most abundant component in human, rat and monkey plasma, with me114 (M2, demethylated) as the major metabolite in human plasma.

CYP3A4 was the major metabolizing enzymes of lenvatinib, followed by CYP1A2 and CYP2B6. In addition, aldehyde oxidase (AO) contributes to the formation of me118 (M2’) and me115 (M3’).

Excretion of Lenvatinib

Was predominantly eliminated in urine in humans, feces in rats and monkeys, with me118 (M2’) as the most significant component in human feces, after dosing of [¹⁴C]lenvatinib mesilate.

About 41.6% of lenvatinib was recovered via biliary excretion in bile duct-cannulated rats after a single oral administration.

Drug-Drug Interaction

Lenvatinib was a potent inhibitor of CYP2C8, UGT1A1 and UGT1A4 with their IC₅₀ in the range of 10.1 to 14 μM, and weak inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A and UGT1A9. Time-dependent inhibition of CYP3A by lenvatinib was observed.

Lenvatinib was not an inducer of CYP1A1, CYP1A2, CYP2C9, CYP2B6, UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and P-gp.

Lenvatinib was a substrate of P-gp and BCRP, but a weak inhibitor of P-gp and BCRP.

Lenvatinib was not a substrate of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, OCT1 and BSEP. Lenvatinib showed concentration-dependent inhibitory effects on OAT1, OAT3, OCT2, OATP1B1, OCT1 and BSEP, with their IC₅₀ in the range of 4.11 to 14.9 μM.

Lenvatinib did not inhibit AO activity.

Single-Dose Toxicity

Single-dose toxicity studies of lenvatinib mesilate were performed in different species following oral administration of lenvatinib mesilate:

●    Rat MNLD: 500 mg/kg

●    Dog MNLD: 1000 mg/kg

●    Monkey MNLD: 1000 mg/kg

Repeated-Dose Toxicity

Repeat-dose toxicity studies were conducted with oral lenvatinib mesilate administration in rats (up to 26 weeks), dogs (up to 4 weeks) and monkeys (up to 39 weeks).

●    For rats: The NOAEL was 0.4 mg/kg/day (0.9 × MRHD), determined by the 26-week study.

●    For monkeys: The NOAEL was 0.1 mg/kg/day (0.1 × MRHD), determined by the 39-week study.

●    Target organs of lenvatinib-mediated toxicity in rats and monkeys were kidneys, duodenum, stomach, pancreas, adrenals (sinusoidal dilation, cortical necrosis, and/or cortical hypertrophy), liver, spleen (lymphoid depletion), thymus (lymphoid depletion and atrophy), pituitary, choroid plexus, heart (rats), femur, teeth (rats), sternum (rats), femoral and sternal marrow (rats; hypocellularity), common bile duct (rats), gallbladder (monkeys), vagina (epithelial atrophy), ovaries, testes, and epididymides.

●    For dogs: The NOAEL was <0.1 mg/kg/day (0.03 × MRHD), determined by the 4-week study.

●    Target organs of lenvatinib-induced toxicity in dogs following 4 weeks of lenvatinib treatment included GI tract, gallbladder, kidneys, testes, and epididymides.

Safety Pharmacology

Both in vitro and in vivo safety pharmacology studies were conducted to assess the effects of lenvatinib on cardiovascular, behavioral, general physiological, and respiratory function:

●    No significant effects were observed on behavior and general physical condition at single oral doses ≤100 mg/kg up to 8 h after administration of lenvatinib.

●    The IC₅₀ for hERG inhibition was 11.89 μM, and no significant effects found on in vitro action potential parameters at concentrations of 1 and 10 μM. In dogs single oral doses of lenvatinib at 6 or 30 mg/kg led to no significant change in cardiovascular parameters.

●    Oral doses ≤ 100 mg/kg also had no effect on respiratory function parameters in rats up to 8 h post-dose.

Genotoxicity

Lenvatinib was neither mutagenic in the in vitro Ames assay, nor clastogenic in the in vitro mouse lymphoma thymidine kinase assay, or the in vivo rat bone marrow micronucleus assay.

Reproductive and Developmental Toxicity

Fertility and early embryonic development: Not conducted

Embryo-fetal development: Embryotoxic, fetotoxic, and teratogenic potentials were demonstrated in rats and rabbits:

●    In rats: The maternal NOAEL was 0.3 mg/kg (1.8 mg/m²); The developmental NOAEL was <0.1 mg/kg.

●    In rabbits: The maternal and NOAEL was 0.1 mg/kg (1.2 mg/m²); The developmental NOAEL was 0.03 mg/kg.

A prenatal/postnatal development: Not conducted:

Juvenile toxicity: Lenvatinib was once daily to SD rats for 8 weeks starting on PND 21:

●    The severely toxic dose was 10 mg/kg (60 mg/m²), and the NOAEL in this study was 0.4 mg/kg (2.4 mg/m²).

●    Target organs of lenvatinib-induced toxicity were generally similar to those observed in adult rats and included the incisors, femur, tibia, sternum, femoral and sternal bone marrow, kidney, GI tract, adrenals, liver, common bile duct, heart, thymus, spleen, pancreas, and choroid plexus.

Lenvatinib can cross the placental barrier in pregnant rats.

Following administration of 3 mg/kg [¹⁴C]lenvatinib to lactating rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

Carcinogenicity

Not conducted.