title: Effects of Ketoconazole on the Pharmacokinetics of Lenvatinib (E7080) in Healthy Participants.
abstract: 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 (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg 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%, Cmaxslightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t½were 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.
authors.affiliation: Eisai, Inc. Woodcliff Lake, NJ, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.affiliation: Eisai, Inc. Woodcliff Lake, NJ, USA.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Aluri
authors.affiliation: Eisai, Inc. Woodcliff Lake, NJ, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Fan
authors.affiliation: Eisai, Inc. Woodcliff Lake, NJ, USA.
authors.forename: Gresel
authors.initials: G
authors.lastname: Martinez
authors.affiliation: GA Thompson Consulting West Chester, OH, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Thompson
authors.affiliation: Eisai, Inc. Woodcliff Lake, NJ, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ren
keywords: CYP3A4; E7080; ketoconazole; lenvatinib; pharmacokinetics