Effect of Rifampicin on the Pharmacokinetics of Lenvatinib in Healthy Adults

BACKGROUND AND OBJECTIVES: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics. METHODS: This Phase I, single-centre, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers. Three regimens were administered over three periods: Period (P) 1 (Days 1–8), P2 (Days 15–22) and P3 (Days 29–50), with a 14-day (first dose) and 28-day (second dose) washout period after lenvatinib mesylate administration (Day 1, Day 15 and Day 43). In P2, a single oral dose of rifampicin (600 mg) was coadministered with lenvatinib. In P3, rifampicin was administered daily (600 mg) for 21 days (Days 29–49). Serial blood samples were collected, and plasma concentrations of total (protein bound + unbound) and free (unbound) lenvatinib and total metabolites (M1, M2, M3 and M5) were measured by validated high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Single-dose rifampicin (P-gp inhibition) increased area under the plasma concentration–time curve from time zero to infinity (AUC(0–∞)) of free and total lenvatinib by 32 and 31 %, respectively. Multiple-dose rifampicin (simultaneous P-gp and CYP3A4 induction) decreased lenvatinib AUC(0–∞) (total: 18 %; free: 9 %). Treatment-emergent adverse events were mild or moderate and occurred in 7 subjects (47 %). CONCLUSION: Lenvatinib exposure was increased by P-gp inhibition; however, based on free concentrations, simultaneous P-gp and CYP3A4 induction results met the prespecified bioequivalence 90 % confidence interval. Overall, the magnitude of these changes was relatively small, and likely not clinically meaningful.