Neratinib-related increases in WBC

Neratinib-related increases in WBC and differentials, platelets and fibrinogen were observed at doses ≥ 3 mg/kg/day in rats and 2 mg/kg/day in dogs and correlated with microscopic findings of inflammation. Target organ toxicities were observed in the liver, lymph nodes, skin, gastrointestinal system, and mammary gland in males. Tubular basophilia in the kidney was also observed in dogs. Findings were either completely reversed or there was a trend of recovery after 28 days of non-dosing. These findings were consistent with the clinical adverse reactions reported in clinical trials, the majority of which (e.g., GI disorders and skin) are likely related the pharmacological inhibition of EGFR, HER2, or HER4. The AUC in rats and dogs in these studies were less than the AUC in patients receiving the recommended dose of 240 mg/day.