Pharmacokinetics and Pharmacodynamics of KT-474, a Novel Selective Interleukin-1...

연구 요약

Pharmacokinetics and Pharmacodynamics of KT-474, a Novel Selective Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degrader, in Healthy Adults.

Clinical and translational science 학술지에 발표된 이 연구는 Agarwal S, McDonald AA, Campbell V 외 연구팀이 수행하였습니다.

이 연구는 'Pharmacokinetics and Pharmacodynamics of KT-474, a Novel Selective Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Degrader, in Healthy Adults.'에 대한 과학적 분석을 제공합니다.

핵심 내용

Interleukin-1 receptor-associated kinase 4 (IRAK4), a key component of the Myddosome complex, mediates signaling through toll-like and interleukin-1 receptors. KT-474, a heterobifunctional IRAK4 degrader, was evaluated in a randomized, double-blind, placebo-controlled Phase 1 trial (NCT04772885) in single (25, 75, 150, 300, 600, 1000, and 1600 mg) and multiple (25, 50, 100, and 200 mg once daily [QD] for 14 days; or 200 mg twice weekly) ascending doses in healthy subjects. The pharmacokinetics of KT-474 and its diastereomers, the pharmacodynamics of KT-474, and the effect of food on KT-474 pharmacokinetics and the pharmacokinetic-pharmacodynamic analysis are presented as additional analyses to supplement the Ackerman et al. publication. KT-474 showed delayed absorption and prolonged elimination. Plasma exposure increased less than dose-proportionally, with single-dose exposure plateauing after the 1000 mg dose. Steady state was achieved after 7 days of daily dosing and resulted in a 3- to 4-fold accumulation in exposure. A significant food effect was observed at the 600 mg dose, with exposure increasing up to 2.57-fold when KT-474 was administered with a high-fat meal. Urinary excretion of KT-474 was < 1%. KT-474 demonstrated robust IRAK4 degradation in blood, with mean reductions of up to 98% observed at the 50-200 mg QD doses, as well as inhibition of ex vivo induction of a broad array of cytokines and chemokines by stimulants lipopolysaccharides and R848. Analysis of the relationship between plasma KT-474 concentration and IRAK4 reduction in blood indicated that plasma concentrations of 4.1-5.3 ng/mL would yield 80% IRAK4 reductions.

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