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Interaction with other medicinal products and other forms of interaction as follows are relevant to the use of lenvatinib monotherapy. Population pharmacokinetic analysis demonstrated that lenvatinib does not significantly affect the pharmacokinetics of either everolimus or pembrolizumab. When using lenvatinib in combination with everolimus or pembrolizumab, also refer to the manufacturer's prescribing information for everolimus or pembrolizumab.
Effect on Cytochrome P450 or UGT Enzymes: Lenvatinib is not considered a strong inducer or inhibitor of cytochrome P450 or uridine 5'-diphospho-glucuronosyl transferase (UGT) enzymes.
Based on simulations from a physiologically based pharmacokinetic model developed for lenvatinib, there is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate) at a dose of 24 mg of lenvatinib. This has also been confirmed in a clinical study determining the effect of lenvatinib on midazolam, in subjects with advanced solid tumors.
Other Chemotherapeutic Agents: Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics (PK) of any of these 3 drugs.
Effect of CYP3A, P-gp, and BCRP Inhibitors: Lenvatinib may be co-administered without dose adjustment with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors.
Effect of P-gp Inhibitors: Lenvatinib may be co-administered without dose adjustment with P-gp inhibitors based on a study in healthy subjects.
Effect of CYP3A and P-gp Inducers: Lenvatinib may be co-administered without dose adjustment with CYP3A and P-gp inducers, based on a study in which healthy subjects were administered repeated doses of rifampicin (600 mg for 21 days) and a single dose of lenvatinib (24 mg, Day 15). The effect of CYP3A induction alone was estimated by comparing the PK parameters for lenvatinib following single and multiple doses of rifampicin. Lenvatinib AUC and Cmax were predicted to decrease by 30% and 15%, respectively, after strong induction in the absence of acute P-gp inhibition. This is supported by a population PK analysis, which found CYP3A4 inducers increased Cl/F by 30%.
Gastric pH Altering Agents: In a population PK analysis of patients receiving lenvatinib up to 24 mg once daily, agents that increase gastric pH (H2 receptor blockers, proton pump inhibitors, antacids) did not have a significant effect on lenvatinib exposure.
In Vitro Studies: Drug metabolizing enzyme and transporter inhibition: In vitro, lenvatinib exhibited an inhibitory effect on CYP2C8 (half-maximal inhibitory concentration [IC50]: 10.1 μmol/L), weak inhibitory effects on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, and virtually no inhibitory effects on CYP2A6 and CYP2E1 in human liver microsomes. Time dependent inhibition of the formation of 1'-hydroxymidazolam from midazolam (CYP3A) by lenvatinib was observed. In human liver microsomes, lenvatinib directly inhibited UGT1A1 and UGT1A4 but showed little or no evidence of inhibition on UGT1A6, UGT1A9, and UGT2B7. Treatment of cultured human hepatocytes with up to 3 μmol/L lenvatinib did not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzyme activities or their mRNA expressions.
Lenvatinib showed minimal or no inhibitory activities toward P-gp-mediated and BCRP-mediated transport activities.
Lenvatinib showed inhibitory effects on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, and the bile salt export pump (BSEP), but minimal or no inhibitory effect on OATP1B3 and multidrug and toxin extrusion 2 (MATE2)-K. Lenvatinib weakly inhibits MATE1.
In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase (AO) activity (IC50>100 μmol/L).
Drug metabolizing enzyme and transporter induction: Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib slightly increased CYP3A enzyme activity (≤1.54-fold) and CYP3A4 mRNA expression (≤1.65-fold). No effects on CYP1A1, CYP1A2, CYP2B6, and CYP2C9 enzyme activities or mRNA expression were observed.
In vitro, lenvatinib did not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7 enzyme activities or mRNA expressions.
Treatment of cultured human hepatocytes with up to 3 μmol/L of lenvatinib showed no induction potency on P-gp mRNA expression.
