jects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively [see DOSAGE AND ADMINISTRATION (2.4), USE IN SPECIFIC POPULATIONS (8.7)].
Effects of Age, Sex, and Race
Based on a population PK analysis, weight, age, sex, and race did not have a significant effect on apparent clearance (Cl/F) of lenvatinib.
Drug Interaction Studies
Effect of Other Drugs on Lenvatinib
CYP3A, P-gp, and BCRP Inhibitors: Ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC by 15% and Cmax by 19% in a dedicated clinical trial.
P-gp Inhibitors: Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single dose) AUC by 31% and Cmax by 33% in a dedicated clinical trial.
CYP3A and P-gp Inducers: Rifampicin (600 mg administered daily for 21 days) decreased lenvatinib (a single 24 mg administered on Day 15) AUC by 18% in a dedicated clinical trial. The Cmax was unchanged.
Effect of Lenvatinib on Other Drugs
CYP3A4 or CYP2C8 Substrates: There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).
In Vitro Studies with CYP or UDP-glucuronosyltransferase (UGT) Substrates: Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, but an increase in lenvatinib exposure that impacts safety is unlikely. Lenvatinib does not inhibit CYP2A6 and CYP2E1.
Lenvatinib induces CYP3A, but a decrease in lenvatinib exposure that impacts efficacy is unlikely. Lenvatinib does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib directly inhibits UGT1A1 and UGT1A4. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on UGT1A6, UGT1A9, UGT2B7, or aldehyde oxidase.
Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
In Vitro Studies with Drug Transporter System Substrates: Lenvatinib inhibits OAT1, OAT3, OCT1, OCT2, OATP1B1, and BSEP. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on OATP1B3.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.
No specific studies with lenvatinib have been conducted in animals to eva luate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvat |
