Scholarlink

Introduction <p>This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of the ketohexokinase inhibitor LY3522348 in healthy participants.</p> Methods <p>This first-in-human phase 1 study evaluated LY3522348, a highly selective, oral dual inhibitor of human ketohexokinase (KHK) isoforms C and A. The study was conducted in two parts: a single-ascending dose (SAD) study and a multiple-ascending dose (MAD) study, including a drug–drug interaction analysis with midazolam. Participants in the SAD study received single oral doses of LY3522348 ranging from 5 to 380&#xa0;mg, while participants in the MAD study received once-daily doses of 50&#xa0;mg, 120&#xa0;mg, and 290&#xa0;mg for 14&#xa0;days.</p> Results <p>A total of 65 healthy participants were included; of these 40 were in the SAD study (placebo = 10; LY3522348: 5&#xa0;mg = 6; 15&#xa0;mg = 6; 50&#xa0;mg = 6; 150&#xa0;mg = 6; 380&#xa0;mg = 6) and 25 in the MAD study (placebo = 6; LY3522348: 50&#xa0;mg = 6; 120&#xa0;mg = 6; 290&#xa0;mg = 7). LY3522348 was well tolerated, with the majority of the reported adverse events being mild. PK analysis showed an approximately dose-proportional increase in LY3522348 exposure, and the half-life ranged from 23.7 to 33.8&#xa0;h. PD analysis indicated a dose-dependent increase in plasma fructose concentrations following the administration of a fructose beverage, supporting the inhibition of fructose metabolism by LY3522348.</p> Conclusions <p>LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism.</p> <p>The study was registered on ClinicalTrials.gov (NCT04559568).</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

LY3522348, A New Ketohexokinase Inhibitor: A First-in-Human Study in Healthy Adults

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月13日

查看全文
  • Tsuyoshi Fukuda,
  • Brian R. Thompson,
  • Bram Brouwers,
  • Hui-Rong Qian,
  • Wei Wang,
  • Bridget L. Morse,
  • Elizabeth Smith LaBell,
  • Timothy B. Durham,
  • Manige Konig,
  • Axel Haupt,
  • Charles T. Benson,
  • James MacKrell

摘要

Introduction

This study aimed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of the ketohexokinase inhibitor LY3522348 in healthy participants.

Methods

This first-in-human phase 1 study evaluated LY3522348, a highly selective, oral dual inhibitor of human ketohexokinase (KHK) isoforms C and A. The study was conducted in two parts: a single-ascending dose (SAD) study and a multiple-ascending dose (MAD) study, including a drug–drug interaction analysis with midazolam. Participants in the SAD study received single oral doses of LY3522348 ranging from 5 to 380 mg, while participants in the MAD study received once-daily doses of 50 mg, 120 mg, and 290 mg for 14 days.

Results

A total of 65 healthy participants were included; of these 40 were in the SAD study (placebo = 10; LY3522348: 5 mg = 6; 15 mg = 6; 50 mg = 6; 150 mg = 6; 380 mg = 6) and 25 in the MAD study (placebo = 6; LY3522348: 50 mg = 6; 120 mg = 6; 290 mg = 7). LY3522348 was well tolerated, with the majority of the reported adverse events being mild. PK analysis showed an approximately dose-proportional increase in LY3522348 exposure, and the half-life ranged from 23.7 to 33.8 h. PD analysis indicated a dose-dependent increase in plasma fructose concentrations following the administration of a fructose beverage, supporting the inhibition of fructose metabolism by LY3522348.

Conclusions

LY3522348 demonstrated a favorable safety profile and well-behaved pharmacokinetics following once-daily oral dosing, and effective inhibition of fructose metabolism.

The study was registered on ClinicalTrials.gov (NCT04559568).