Abstract
The purpose of this study was to evaluate the toxicity of lenvatinib, VEGF receptor inhibitor, in juvenile rats.
In the DRF study, lenvatinib was administered orally once daily for 2 weeks to Sprague-Dawley rats at doses of 0, 0.2, 0.4, 1 or 5 mg/kg/day from postnatal day (PND) 7 or at doses of 0, 0.4, 1, 5 or 25 mg/kg/day from PND 21 followed by a 2-week recovery period. The toxicologic profile of lenvatinib was similar to that in adult rats in both group of rats in this study, but the toxicity in PND 7 rats was more severe compared to PND 21 rats and mortality was observed in PND 7 rats. The cause of death was considered due to severe intestinal change and peritonitis. The histopathologic changes in duodenal glands were observed in only PND 21 rats.
In the main study, rats were administered lenvatinib via oral gavage at doses of 0, 0.4, 2 or 10 mg/kg/day for 8 weeks from PND 21 followed by a 4-week recovery period. At 2 mg/kg/day and above, severe growth retardation (suppression of body weight gain with decreased food consumption), which correlated with a decrease in the width and/or length of femur and tibia, delayed physical development (prepuce separation and vaginal opening at 10/mg/kg/day) and reproductive organ immaturity was observed.
At 10 mg/kg/day, mortality observed with histological changes in the gastrointestinal tract, choroid plexus, and adrenals that were similar to previous findings in adult rats. Toxicities were mostly reversible, although residual changes were observed at the end of the 4-week recovery period. No toxicologically significant change was observed at 0.4 mg/kg/day.
