Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants

Background: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein. Methods: In this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18-55 years; N=18) were randomized to one of two sequences (ketoconazole→placebo or vice versa). Ketoconazole (400mg) or placebo was administered orally once daily for 18 days; a 5mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry. Results: Systemic exposure to lenvatinib increased slightly (15-19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration-time curve (AUC) was within the prespecified bioequivalence interval of 80-125%, Cmax slightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t1/2 were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). Conclusions: Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful.