Study design
OCA, pruritus, PK/PD, SAD
This study was conducted using a randomized (in each dose cohort), double-blind, placebo-controlled, dose-escalation design consisting of a single ascending dose (SAD; Part 1), multiple doses (Part 2), and food effect (Part 3). In part 1, the subjects randomly received a single dose of TQA3526 or placebo in the fasted state after an overnight fast at a ratio of 2:0 (1 mg) or 8:2 (2, 5, and 10 mg). Furthermore, subjects in the 10 mg cohort repeated the study under the fed state after a 10- or 19-day washout period to assess the effect of a high-fat diet on the PK profile of TQA3526 as part 3. Part 2 contained two cohorts. In the ninth cohort, study participants randomly received multiple oral doses of 2 mg TQA3526 or placebo once daily for 7 days under the fasted state at a ratio of 8:4. In the tenth cohort, study participants randomly received continuous multiple oral doses of 0.2 mg (10 days), 0.5 mg (10 days) and 1 mg (10 days) TQA3526 or placebo once daily at a ratio of 8:4.Subjects were admitted to the Clinical Trial Center the day before drug administration and discharged 72 h after the last drug administration. During the confinement period, the subjects were provided standardized meals (except for the high-fat diet in the 10 mg dose cohort) to minimize the effect of food on PK/PD evaluations.For the SAD study, a maximum recommended starting dose of 105 mg was calculated based on the standard 10-fold safety margin from the beagle dog no-observed-adverse-effect-level (NOAEL) exposure study, per the regulatory guidelines. However, 0.5, 1, and 2 mg were estimated to be effective doses, as TQA3526 could have the same efficacy as 1/5–1/10 dosage of OCA (5 or 10 mg/day) based on preclinical efficacy studies. Therefore, a single dose range of 1–50 mg was chosen, and multiple doses were set at 2 mg and 5 + 10 + 20 mg originally. As most subjects experienced pruritus after multiple doses of 2 mg, the single dose range was adjusted to 1–10 mg and 5 + 10 + 20 mg was replaced by 0.2 + 0.5 + 1 mg for safety concerns.