BACKGROUND AND OBJECTIVES: Ropanicant hydrochloride (previously known as SUVN-911, hereinafter referred to as ropanicant) is a novel alpha4 beta2 nicotinic acetylcholine receptor (α4β2 nAchR) antagonist being developed for the treatment of major depressive disorder. The objectives of the present studies were to evaluate the safety, tolerability, and pharmacokinetics of ropanicant after single and multiple ascending doses and to evaluate the effect of food, sex, and age on its pharmacokinetics in healthy subjects. METHODS: Two phase I studies have been conducted for ropanicant. Study 1 is a randomized, double-blind, placebo-controlled, first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (0.5, 6, 15, 30, and 60 mg) and multiple ascending doses (15, 30, and 45 mg) of ropanicant administered orally for 14 days to healthy male subjects. In Study 2, the effect of food, sex, and age on ropanicant pharmacokinetics was evaluated following a single 30-mg oral dose. RESULTS: Ropanicant at single doses up to 60 mg and multiple doses up to 45 mg once daily was found to be safe and well tolerated in healthy subjects. The most frequently reported adverse events were headache and nausea. Ropanicant exposures were more than dose proportional following single and multiple administrations. Urinary excretion of unchanged ropanicant was low across the doses. Upon multiple dosing, 1.5- to 2.5-fold higher exposures for maximum concentration and 1.6- to 4.0-fold higher exposures for area under the concentration-time curve from time 0-24 h were observed on day 14 as compared with day 1. Sex had an effect on the pharmacokinetics of ropanicant as a 64% higher area under the concentration-time curve from time 0 to 24 h and a 26% higher maximum concentration was observed in female adults when compared with male adults. Plasma exposures were comparable in fasted versus fed conditions and in adult versus elderly subjects. CONCLUSIONS: Ropanicant was found to be safe and well tolerated following single and multiple oral administrations in healthy subjects. Ropanicant showed nonlinear pharmacokinetics and accumulation following multiple dosing. Urinary excretion represents an insignificant elimination pathway for ropanicant. Ropanicant pharmacokinetics were sex dependent, and food and age had no effect on its pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03155503 and NCT03551288.
BACKGROUND AND OBJECTIVES: Ropanicant hydrochloride (previously known as SUVN-911, hereinafter referred to as ropanicant) is a novel alpha4 beta2 nicotinic acetylcholine receptor (α4β2 nAchR) antagonist being developed for the treatment of major depressive disorder. The objectives of the present studies were to evaluate the safety, tolerability, and pharmacokinetics of ropanicant after single and multiple ascending doses and to evaluate the effect of food, sex, and age on its pharmacokinetics in healthy subjects. METHODS: Two phase I studies have been conducted for ropanicant. Study 1 is a randomized, double-blind, placebo-controlled, first-in-human study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (0.5, 6, 15, 30, and 60 mg) and multiple ascending doses (15, 30, and 45 mg) of ropanicant administered orally for 14 days to healthy male subjects. In Study 2, the effect of food, sex, and age on ropanicant pharmacokinetics was evaluated following a single 30-mg oral dose. RESULTS: Ropanicant at single doses up to 60 mg and multiple doses up to 45 mg once daily was found to be safe and well tolerated in healthy subjects. The most frequently reported adverse events were headache and nausea. Ropanicant exposures were more than dose proportional following single and multiple administrations. Urinary excretion of unchanged ropanicant was low across the doses. Upon multiple dosing, 1.5- to 2.5-fold higher exposures for maximum concentration and 1.6- to 4.0-fold higher exposures for area under the concentration-time curve from time 0-24 h were observed on day 14 as compared with day 1. Sex had an effect on the pharmacokinetics of ropanicant as a 64% higher area under the concentration-time curve from time 0 to 24 h and a 26% higher maximum concentration was observed in female adults when compared with male adults. Plasma exposures were comparable in fasted versus fed conditions and in adult versus elderly subjects. CONCLUSIONS: Ropanicant was found to be safe and well tolerated following single and multiple oral administrations in healthy subjects. Ropanicant showed nonlinear pharmacokinetics and accumulation following multiple dosing. Urinary excretion represents an insignificant elimination pathway for ropanicant. Ropanicant pharmacokinetics were sex dependent, and food and age had no effect on its pharmacokinetics. CLINICAL TRIAL REGISTRATION: NCT03155503 and NCT03551288.