st growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. 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.
12.2 Pharmacodynamics
Cardiac Electrophysiology
A single 32 mg dose (1.3 times the recommended daily dose) of lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in clinical studies [see WARNINGS AND PRECAUTIONS (5.9)].
12.3 Pharmacokinetics
Absorption: After oral administration of LENVIMA, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food 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 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 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
Distribution: In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μg/mL).
Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP).
Elimination: Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of lenvatinib was approximately 28 hours.
Metabolism: CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.
Excretion: Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.
Specific Populations:
Renal Impairment
The pharmacokinetics of lenvatinib following a single 24 mg dose were eva luated in subjects with mild (CLcr 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr <30 mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal disease were not studied. After a single 24 mg oral dose of LENVIMA, the AUC0-inf for subjects with renal impairment were similar compared to those for healthy subjects [see DOSAGE AND ADMINISTRATION (2.4), WARNINGS AND PRECAUTIONS (5.6), USE IN SPECIFIC POPULATIONS (8.6)].
Hepatic Impairment
The pharmacokinetics of lenvatinib following a single 10 mg dose of LENVIMA were eva luated in subjects with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of a single 5 mg dose were eva luated in subjects with severe (Child-Pugh C) hepatic impairment. Compared to sub |
