Scholarlink

Introduction <p>Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1.</p> Methods <p>This 2-part Phase I trial enrolled healthy participants aged 18–55&#xa0;years. Part 1 consisted of 2 sub-parts. Part 1a was a double-blind, randomized, single ascending dose (SAD) study with 6 cohorts of 8 participants each randomized 3:1 to single oral dose of eclitasertib (10&#xa0;mg, 30&#xa0;mg, 100&#xa0;mg, 200&#xa0;mg, 400&#xa0;mg, or 800&#xa0;mg) or placebo. Part 1b was an open-label, randomized, three-sequence, cross-over design study to evaluate the relative bioavailability of the prototype formulation versus the drug substance and the effect of food in an independent cohort of 10 participants. Part 2 was a double-blind, randomized, multiple ascending dose study (MAD) with 4 cohorts of 10 participants each randomized 4:1 to receive eclitasertib (50&#xa0;mg, 100&#xa0;mg, 200&#xa0;mg, or 600&#xa0;mg once daily) or placebo orally for 14&#xa0;days. Incidence of adverse events (AEs; primary outcome), PK (secondary outcome), and PD properties (exploratory outcome; assessed by reduction in levels of S166 phosphorylated RIPK1) were evaluated.</p> Results <p>Single and multiple oral doses of eclitasertib were well tolerated, with no study drug-related severe or serious AEs reported. Medical device-site reactions (includes AEs classified as device-site reaction, vessel puncture-site hematoma/pain, catheter-site pain/hematoma and catheter-site-related reactions) and headache were the most commonly reported AEs in both parts. Overall, the median <i>T</i><sub>max</sub> ranged from 3 to 4&#xa0;h. <i>C</i><sub>max</sub> and AUC increased sub-dose proportionally. Administration of eclitasertib 100&#xa0;mg following a high-fat meal did not significantly impact its bioavailability. At doses of 100&#xa0;mg and above,&#xa0;&gt;&#xa0;90% inhibition of RIPK1 phosphorylation in human peripheral blood mononuclear cells was observed with eclitasertib at 12&#xa0;h post-dose in both SAD and MAD studies.</p> Conclusions <p>Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation.</p> Trial registration <p>EudraCT 2019-001350-25.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A Randomized Phase I Trial Evaluating Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eclitasertib, a RIPK1 Inhibitor, in Healthy Participants

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月19日

查看全文
  • Christine Farenc,
  • Pierre-Francois Clot,
  • Salvatore Badalamenti,
  • Annie J. Kruger,
  • Robert J. Pomponio,
  • Tillmann Krahnke,
  • Heribert Staudinger,
  • Yong Lin

摘要

Introduction

Receptor-interacting protein kinase 1 (RIPK1) is a master regulator of inflammation and necroptotic cell death and is implicated in the pathogenesis of several inflammatory and neurodegenerative diseases. This first-in-human study assessed the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of eclitasertib, a selective, peripherally-restricted, oral inhibitor of RIPK1.

Methods

This 2-part Phase I trial enrolled healthy participants aged 18–55 years. Part 1 consisted of 2 sub-parts. Part 1a was a double-blind, randomized, single ascending dose (SAD) study with 6 cohorts of 8 participants each randomized 3:1 to single oral dose of eclitasertib (10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg) or placebo. Part 1b was an open-label, randomized, three-sequence, cross-over design study to evaluate the relative bioavailability of the prototype formulation versus the drug substance and the effect of food in an independent cohort of 10 participants. Part 2 was a double-blind, randomized, multiple ascending dose study (MAD) with 4 cohorts of 10 participants each randomized 4:1 to receive eclitasertib (50 mg, 100 mg, 200 mg, or 600 mg once daily) or placebo orally for 14 days. Incidence of adverse events (AEs; primary outcome), PK (secondary outcome), and PD properties (exploratory outcome; assessed by reduction in levels of S166 phosphorylated RIPK1) were evaluated.

Results

Single and multiple oral doses of eclitasertib were well tolerated, with no study drug-related severe or serious AEs reported. Medical device-site reactions (includes AEs classified as device-site reaction, vessel puncture-site hematoma/pain, catheter-site pain/hematoma and catheter-site-related reactions) and headache were the most commonly reported AEs in both parts. Overall, the median Tmax ranged from 3 to 4 h. Cmax and AUC increased sub-dose proportionally. Administration of eclitasertib 100 mg following a high-fat meal did not significantly impact its bioavailability. At doses of 100 mg and above, > 90% inhibition of RIPK1 phosphorylation in human peripheral blood mononuclear cells was observed with eclitasertib at 12 h post-dose in both SAD and MAD studies.

Conclusions

Single and repeated doses of eclitasertib were well tolerated in healthy participants and potently inhibited RIPK1 activation.

Trial registration

EudraCT 2019-001350-25.