2.2. Study design and sample collection

The SAD and MAD studies were randomized, double‐blind, placebo‐controlled, dose escalation, and parallel group comparison studies. In the SAD study, nine fasted healthy subjects were randomly assigned in a 2:1 ratio to receive either a single oral dose of 0.5, 1, 2, 5, 10 and 20 mg of dotinurad (n = 6) or placebo (n = 3). From the point of ethical consideration, the number of subjects in the placebo group was set at the half of the dotinurad treated groups (n = 3) as the minimum number of subjects that allows comparison of safety during hospitalization in each dotinurad treated group. Placebo formulation was composed of more proportion of lactose hydrate instead of dotinurad. The effect of food on the PK of dotinurad was evaluated at 5‐mg dose with the same subjects in the fasted dosing study. In the MAD study, nine fed healthy subjects received either 2 or 5 mg of dotinurad (n = 6) or placebo (n = 3) once daily over 7 days.

In the SAD study, blood samples were collected at 0 (30 min before dosing), 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing to determine the plasma dotinurad concentration as well as SUA and serum creatinine concentrations. In the MAD study, blood samples were collected at 0 (only at day 0), 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours after dosing in days 0, 3, 6, and only at 12 and 24 hours in days 1, 2, 4, 5, and additionally at 36, 48, and 72 hours in day 6. Urine samples were collected for 24 hours before dosing and 0‐6, 6‐12, 12‐24, 24‐36, and 36‐48 hours after dosing in the SAD study, or every 24 hours before and after dosing, and up to 72 hours only after the last dose in the MAD study, to determine dotinurad, urate, and creatinine concentrations in the urine.