British journal of clinical pharmacology · 2026
Safety, pharmacodynamics and pharmacokinetics of a novel JAK1-selective inhibitor, IN-115314, in healthy participants: A first-in-human study.
СтатьяНазвание 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.
Huh Ki Young, Kang Jaegu, Jang Haerim, Kang Deborah, Jang In-Jin, Lee Seung Hwan
Аннотация
AIMS: Selective JAK1 inhibition can control inflammation in immune-mediated diseases with reduced haematological toxicity. IN-115314, a selective JAK1 inhibitor, was evaluated in a first-in-human, randomized, double-blind, placebo-controlled study in healthy participants for safety, pharmacokinetics (PK) and pharmacodynamics (PD).
METHODS: In six cohorts, participants received IN-115314 or placebo as single oral doses of 2.5 and 10 mg (cohorts 1 and 2) or single and 7-day multiple doses of 25, 50, 100 and 200 mg (cohorts 3-6). JAK1 and JAK2 inhibition was evaluated by changes from baseline in IL-6-induced phosphorylated STAT1 (pSTAT1) and GM-CSF-induced pSTAT5. PD samples were collected up to 24 h post-dose after a single dose and at steady state, whereas blood and urine PK samples for IN-115314 and IN-116118 were collected up to 72 h, with dose-proportionality assessment.
RESULTS: Of 55 randomized participants, 54 completed the study. Adverse events occurred in 13 of 44 (29.5%) IN-115314 recipients and 2 of 11 (18.2%) placebo recipients; all were mild, with no serious adverse events. IN-115314 demonstrated significant, dose-dependent JAK1 inhibition, with maximal inhibition (97.5%) at 200 mg. Plasma concentrations and JAK1 inhibition were well described by a sigmoidal Imax model. JAK2 inhibition was minimal, with no relevant changes in absolute neutrophil or reticulocyte counts. IN-115314 was rapidly absorbed and eliminated, with a terminal half-life of 0.57-2.46 h, supra-dose-proportional but time-invariant PKs and minimal accumulation (accumulation ratio 1.12-1.52).
CONCLUSIONS: IN-115314 was safe, well tolerated and showed rapid, dose-dependent JAK1 inhibition consistent with its PK profile. (ClinicalTrials.gov registration no.: NCT04297865).
METHODS: In six cohorts, participants received IN-115314 or placebo as single oral doses of 2.5 and 10 mg (cohorts 1 and 2) or single and 7-day multiple doses of 25, 50, 100 and 200 mg (cohorts 3-6). JAK1 and JAK2 inhibition was evaluated by changes from baseline in IL-6-induced phosphorylated STAT1 (pSTAT1) and GM-CSF-induced pSTAT5. PD samples were collected up to 24 h post-dose after a single dose and at steady state, whereas blood and urine PK samples for IN-115314 and IN-116118 were collected up to 72 h, with dose-proportionality assessment.
RESULTS: Of 55 randomized participants, 54 completed the study. Adverse events occurred in 13 of 44 (29.5%) IN-115314 recipients and 2 of 11 (18.2%) placebo recipients; all were mild, with no serious adverse events. IN-115314 demonstrated significant, dose-dependent JAK1 inhibition, with maximal inhibition (97.5%) at 200 mg. Plasma concentrations and JAK1 inhibition were well described by a sigmoidal Imax model. JAK2 inhibition was minimal, with no relevant changes in absolute neutrophil or reticulocyte counts. IN-115314 was rapidly absorbed and eliminated, with a terminal half-life of 0.57-2.46 h, supra-dose-proportional but time-invariant PKs and minimal accumulation (accumulation ratio 1.12-1.52).
CONCLUSIONS: IN-115314 was safe, well tolerated and showed rapid, dose-dependent JAK1 inhibition consistent with its PK profile. (ClinicalTrials.gov registration no.: NCT04297865).