Permitted Daily Exposure of the Androgen Receptor Antagonist Flutamide.

This report aims to determine the permitted daily exposure (PDE) of flutamide, an androgen receptor blocker, as directed by guideline EMA/CHMP/CVPM/SWP/169430/2012 that came into effect on June 2015. A literature review was conducted to identify toxicity studies of flutamide. Hazards and sensitive endpoints were determined. Based on the no adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) reported from both reproductive, developmental, and 28-day toxicity studies the PDE was calculated. Most of the toxicity studies converge toward a NOAEL of 1 mg/kg/d that translates to a PDE of 0.1 mg/d. However, taking into consideration the worst case scenarios for additional safety a PDE of 0.025 mg/d (25 μg/d) was calculated based on a reported NOAEL of 0.25 mg/kg/d. A PDE of 0.05 mg/d (50 μg/d) was also calculated from reproductive/developmental toxicity studies, which is in close agreement with the PDE from the 28-day toxicity studies. Considering the lowest PDE of 0.025 mg/d, residual flutamide at this dose is unlikely to pose any risk to humans. Nonmonotonic dose response (NMDR) effects of flutamide were not supported by literature. Oral route of administration was considered.