Bioequivalence clinical trial simulation: a case study of apalutamide administered in applesauce versus whole tablets

Patients who have difficulty swallowing apalutamide tablets may benefit from administration in a food vehicle that is easier to swallow. In a previous single-dose study conducted in healthy male volunteers ( n = 12) a larger peak exposure was observed (+ 27.6%) for apalutamide in applesauce compared with whole tablets, despite a comparable extent of exposure (+ 5%). However, because apalutamide is taken daily which results in a 3–5 fold accumulation ratio, the observed 27.6% difference in peak exposure with single-dose administration may be reduced with multiple doses. To evaluate the difference in peak exposure under daily administration of apalutamide, bioequivalence trial simulations assessing the probability of success in demonstrating bioequivalence between the two administration methods after repeat dose and single-dose administration were conducted. Simulated pharmacokinetic (PK) profiles for the reference treatment were based on an established population PK model for apalutamide. Simulated profiles for test treatment were based on the same model but with a treatment covariate fitted to the PK observations of the single-dose study. The present analysis found that > 85% of simulated steady-state bioequivalence trials with 10 subjects or more comparing daily apalutamide administration in applesauce versus whole tablets met the 80–125% criteria for bioequivalence for both maximum concentration (C max,ss ) and area under the concentration curve at steady state (AUC 0–24 h,ss ). Results of these clinical trial simulations suggest that the daily administration of 240 mg apalutamide in applesauce is bioequivalent to whole tablet administration.