Single-dose and steady-state pharmacokinetic studies of S-equol, a potent nonhormonal, estrogen receptor β-agonist being developed for the treatment of menopausal symptoms

In Brief Objective: S-equol is produced from the biotransformation of the soy isoflavone daidzein. Clinical trials have shown that being an equol producer reduces menopausal symptoms. As part of a drug development program, S-equol was synthesized in pure form. In this report, we describe its safety, tolerability, and pharmacokinetics. Methods: Two randomized, double-blind, placebo-controlled clinical trials were carried out in healthy volunteers: a single-rising dose (10-320 mg) study in 61 participants and a 14-day multirising dose (10-160 mg, BID) study in 40 participants. Results: S-equol was well tolerated by all participants; there were no significant drug-related adverse events. S-equol was rapidly absorbed, with time of peak plasma concentration (Tmax) ranging from 1.5 to 3 hours after a single dose. Less than 1% of total S-equol in plasma appeared as the unconjugated form, the majority being conjugated forms of S-equol. Plasma area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. At the 20-mg single dose, a crossover study showed that food intake significantly decreased Cmax but not AUC for total S-equol; Cmax and AUC of unconjugated S-equol were not significantly affected. Conclusions: These studies in healthy participants establish the first report on the plasma and urine levels of unconjugated S-equol after oral dosing. The rapid absorption and pharmacokinetic parameters show that S-equol exposure is linear with dose. There were no significant drug-related adverse events even at the highest dose tested of 320 mg; these data provide the information for dose selection for efficacy studies in postmenopausal women. Results from single-dose and 14-day repeat dose phase 1 clinical trials demonstrate the safety of S-equol in men and women up to the highest doses tested in these studies. Maximum Concentration (Cmax) and area under the curve (AUC) for unconjugated and total S-equol were linear with dose, with steady state achieved after 2 days of twice-daily dosing.