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Pharmacology: Pharmacodynamics: Mechanism of Action: Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor (PDGF) receptor PDGFRα; KIT; and RET.
In addition, lenvatinib had selective, direct antiproliferative activity in hepatocellular cell lines dependent on activated FGFR signaling, which is attributed to the inhibition of FGFR signaling by lenvatinib.
In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
QT Assessment: A single 32 mg dose of lenvatinib did not prolong the QTc interval based on results from a thorough QT study in healthy subjects.
Pharmacokinetics: Absorption: Lenvatinib is rapidly absorbed after oral administration with tmax typically observed from 1 to 4 hours post dose. Food does not affect the extent of absorption, but slows the rate of absorption. When administered to healthy subjects with food, peak plasma concentrations are delayed by 2 hours.
In subjects with solid tumors administered single and multiple doses of lenvatinib once daily, exposure to lenvatinib (Cmax and AUC) increase in direct proportion to the administered dose over the range of 3.2 to 32 mg. Lenvatinib displays minimal accumulation at steady-state. Over this range, the median accumulation index (Rac) ranged from 0.96 (20 mg) to 1.54 (6.4 mg).
Distribution: In vitro binding of lenvatinib to human plasma proteins is high and ranged from 98% to 99% (0.3 - 30 μg/mL, mesilate). This binding was mainly to albumin with minor binding to α1-acid glycoprotein and γ-globulin. A similar plasma protein binding (97% to 99%) with no dependencies on lenvatinib concentrations (0.2 to 1.2 μg/mL) was observed in plasma from hepatically impaired renally impaired, and matching healthy subjects.
In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 - 10 μg/mL, mesilate).
Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K or the BSEP.
Biotransformation: In vitro, cytochrome P450 3A4 was the predominant (>80%) cytochrome isoform involved in the P450-mediated metabolism of lenvatinib. In vivo, inducers and inhibitors of CYP3A4 had a minimal effect on lenvatinib exposure (see Interactions).
In human liver microsomes, the demethylated form of lenvatinib (M2) was identified as the main metabolite. M2' and M3', the major metabolites in human feces, were formed from M2 and lenvatinib, respectively, by AO. In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of the radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional 2.5%. Based on AUC0-inf, lenvatinib accounted for 60% and 64% of the total radioactivity in plasma and blood, respectively.
Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolized in humans. The main metabolic pathways in humans were identified as oxidation by AO, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (eg, glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerization). These in vivo metabolic routes align with the data provided in the in vitro studies using human biomaterials.
Elimination: Plasma concentrations decline bi-exponentially following Cmax. The terminal exponential half-life of lenvatinib is about 28 hours.
Following administration of radiolabeled lenvatinib to 6 subjects with solid tumors, approximately two-thirds and one-fourth of the radiolabel were eliminated in the feces and urine, respectively. The M2 metabolite was the predominant analyte in excreta (~5% of the dose) with lenvatinib the second most prominent (~2.5%).
Special Populations: Hepatic Impairment: The PK of lenvatinib following a single 10 mg dose were evaluated in 6 subjects with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5 mg dose was evaluated in 6 subjects with severe hepatic impairment (Child-Pugh C). Eight healthy, demographically matched subjects served as controls and received a 10 mg dose.
The median half-life was comparable in subjects with mild, moderate, and severe hepatic impairment as well as those with normal hepatic function and ranged from 26 hr to 31 hr.
The percentage of the dose of lenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).
Lenvatinib exposure, based on dose-adjusted AUC0-t and AUC0-inf data, was 119%, 107%, and 180% of normal for subjects with mild, moderate, and severe hepatic impairment, respectively. It is unknown whether there is a change in the plasma protein binding in hepatically impaired subjects. See Dosage & Administration for dosing recommendation.
Renal Impairment: The PK of lenvatinib following a single 24 mg dose were evaluated in 6 subjects each with mild, moderate, and severe renal impairment, and compared to 8 healthy, demographically matched subjects. Creatinine clearance ranges were defined as follows: creatinine clearance of ≥81 mL/min for normal, creatinine clearance of 50 to 80 mL/min for mild renal impairment, creatinine clearance of 30 to 49 mL/min for moderate renal impairment, and creatinine clearance of 15 to 29 mL/min for severe renal impairment. Subjects with end stage renal disease were not studied. Lenvatinib exposure, based on AUC0-inf data, was 101%, 90%, and 122% of normal for subjects with mild, moderate and severe renal impairment, respectively, compared to normal subjects. It is unknown whether there is a change in the plasma protein binding in renally impaired subjects. See Dosage & Administration for dosing recommendation.
Gender: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), gender had no significant effects on apparent clearance Cl/F.
Elderly (65 years of age and above): Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), age had no significant effects on Cl/F.
Race: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), race (Japanese vs. other, Caucasian vs other) had no significant effects on Cl/F.
Tumor Type: Tumor type had no significant effect on clearance (Cl/F), based on population pharmacokinetic analysis of patients receiving: up to 24 mg levatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC).
Pediatric Population: Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily as monotherapy (DTC), up to 18 mg once daily in combination with 5 mg everolimus (RCC), and up to 20 mg once daily in combination with pembrolizumab (RCC and EC), age had no significant effects on Cl/F in pediatric patients.
Genomic Assessment of Lenvatinib Pharmacokinetic Parameters: Because of lenvatinib's extensive metabolism, the effect of selected drug metabolizing enzyme phenotypes on lenvatinib clearance was investigated using data derived from the Affymetrix drug-metabolizing enzyme and transporter (DMET Plus) microarray genotyping platform. None of the phenotypes for CYP3A5, CYP1A2, CYP2A6, and CYP2C19 had a significant impact on lenvatinib clearance.
