title: Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers.
abstract: OBJECTIVE
  To evaluate the effect of formulation and a high-fat meal on the pharmacokinetics of orally administered lenvatinib (E7080).
  
  
  METHODS
  Lenvatinib 10-mg capsule and tablet.
  
  
  METHODS
  Pharmacokinetics and safety of a single 10-mg lenvatinib dose were evaluated in healthy subjects in two randomized, two-period, crossover, phase 1, bioavailability trials. The first compared a new capsule formulation with an older tablet formulation (n = 20 subjects); the second evaluated the influence of a standard high-fat meal on the relative bioavailability of the capsule formulation (n = 16 subjects). Geometric least squares mean ratios of AUC0-∞, maximum observed concentration (Cmax), and AUC0-t were determined. tmax, tlag (food effect only), and t1/2,z were also calculated, and descriptive statistics were provided.
  
  
  RESULTS
  A total of 36 healthy volunteers were enrolled in the two studies (mean ages 29 and 33 years). In the formulation study, AUC0-∞ and AUC0-t of the capsule formulation were ~ 10% less than the tablet formulation, and Cmax for the capsule formulation was ~ 14% lower. 90% Confidence intervals (CIs) for both AUCs were within the 80 - 125% CI, which is generally considered to denote bioequivalence, while the lower bound of the interval for Cmax was 79.8%. tmax and t1/2,z were comparable. For the capsule formulation, the mean (%CV) t1/2,z was 27.6 hours (27.3) and the median (range) tmax was 2.0 hours (2 - 4). In the food effect study, lenvatinib's AUC0-∞ and AUC0-t increased ~ 6% and 4% with the high-fat meal. Cmax following a high-fat meal was 5% lower than following administration in the fasted state. Administration with food delayed lenvatinib's tmax (2 vs. 4 hours). 90% CIs for AUCs were within the 80 - 125% CI, while the CI for Cmax was 72.1 - 126.4%. The single 10-mg dose demonstrated an acceptable tolerability profile; treatment-emergent adverse events occurred in 9 subjects (25%) overall and were typically mild in severity.
  
  
  CONCLUSIONS
  These studies show that a new capsule formulation produces slightly lower exposure (~10 - 14%) to lenvatinib compared with the original tablet formulation, and that oral administration with a high-fat meal does not significantly affect exposure, although absorption is delayed. Thus, lenvatinib can be administered without regard to the timing of meals.
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Aluri
authors.forename: Jean
authors.initials: J
authors.lastname: Fan
authors.forename: Gresel
authors.initials: G
authors.lastname: Martinez
authors.forename: Min
authors.initials: M
authors.lastname: Ren
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib