Psychopharmacology · 2025
Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Appel Lieuwe, Risinger Robert, Wall Anders, Murck Harald, Liu Shuang, Antoni Gunnar, Lane Roger
Аннотация
RATIONALE: Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission.
OBJECTIVES: This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET).
METHODS: Part A was a double-blinded, randomized, placebo-controlled, sequential SAD study with seven sequential dose panels (0.5-150 mg) where subjects in each panel received either a single oral dose of CSTI-500 (n=6) or placebo (n=2). Part B was an open-label, single-dose PET study to assess the peak and duration of SERT (n=4) and DAT (n=5) striatal occupancies, using the radioligands [11C]MADAM and [11C]PE2I, respectively.
RESULTS: The maximum tolerable acute single-dose of CSTI-500 was determined as 100 mg. No serious adverse events occurred. The median maximum CSTI-500 concentrations were attained at 1-2 hours post-dose (h pd); the estimated plasma elimination half-life was 44-50 h pd. Subsequent to a single-dose of 100 mg CSTI-500, mean striatal SERT occupancy was 72% and 62% at 4-6 and 24 h pd, respectively. Mean striatal DAT occupancy was 36% and 31% at 4-9 and 24 h pd, respectively.
CONCLUSIONS: CSTI-500 is a potent monoamine TRI with substantial striatal SERT and moderate DAT occupancies in healthy subjects. Together with promising safety-tolerability and pharmacokinetics profiles, the continued clinical development of CSTI-500 is strongly supported.
OBJECTIVES: This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET).
METHODS: Part A was a double-blinded, randomized, placebo-controlled, sequential SAD study with seven sequential dose panels (0.5-150 mg) where subjects in each panel received either a single oral dose of CSTI-500 (n=6) or placebo (n=2). Part B was an open-label, single-dose PET study to assess the peak and duration of SERT (n=4) and DAT (n=5) striatal occupancies, using the radioligands [11C]MADAM and [11C]PE2I, respectively.
RESULTS: The maximum tolerable acute single-dose of CSTI-500 was determined as 100 mg. No serious adverse events occurred. The median maximum CSTI-500 concentrations were attained at 1-2 hours post-dose (h pd); the estimated plasma elimination half-life was 44-50 h pd. Subsequent to a single-dose of 100 mg CSTI-500, mean striatal SERT occupancy was 72% and 62% at 4-6 and 24 h pd, respectively. Mean striatal DAT occupancy was 36% and 31% at 4-9 and 24 h pd, respectively.
CONCLUSIONS: CSTI-500 is a potent monoamine TRI with substantial striatal SERT and moderate DAT occupancies in healthy subjects. Together with promising safety-tolerability and pharmacokinetics profiles, the continued clinical development of CSTI-500 is strongly supported.