脂化的限制:将塞马鲁肽从每周一次用药改为每月一次用药

Eric L Schneider, John A Hangasky, Rocio del Valle Fernandez, Gary W Ashley, Daniel V Santi
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摘要

这项研究的目的是开发一种脂化肽塞马鲁肽的长效制剂,人体可每月服用一次。塞马鲁肽通过可裂解连接剂附着在直径为 50 μ 的水凝胶微球上,预计体内释放半衰期约为一个月。单次皮下注射后,测定了正常小鼠体内释放的塞马鲁肽的药代动力学参数,并测定了饮食诱导肥胖小鼠的体重减轻情况。结果用于模拟微球释放的塞马鲁肽在人体中的药代动力学。在 pH 值为 7.4 的条件下,通过可裂解连接剂系在微球上的塞马鲁肽可完全释放,体外半衰期约为 55 天。释放出的塞马鲁肽在体内的半衰期约为30天,在饮食诱导的肥胖小鼠体内单次给药可在1个月内使体重减轻20%,在统计学上与每天给药两次的塞马鲁肽效果相同。模拟结果表明,微球-塞马鲁肽允许人体每月服用一次。本文所述的微球-塞马鲁肽共轭物应适合人体每月一次给药,同样的方法也能使其他脂化肽从每周一次给药转变为每月一次给药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The limitation of lipidation: conversion of semaglutide from once-weekly to once-monthly dosing
The objective of this work was to develop a long-acting form of the lipidated peptide semaglutide that can be administered to humans once-monthly. Semaglutide was attached to 50 μ diameter hydrogel microspheres by a cleavable linker with an expected in vivo release half-life of about one-month. After a single subcutaneous dose, the pharmacokinetic parameters of released semaglutide were determined in normal mice and the bodyweight loss was determined in diet induced obese mice. The results were used to simulate the pharmacokinetics of semaglutide released from the microspheres in humans.Semaglutide tethered to microspheres by a cleavable linker could be completely released with an in vitro half-life of ~55 days at pH 7.4. The in vivo half-life of released semaglutide was ~30 days, and a single dose in diet-induced obese mice resulted in a lean-sparing body weight loss of 20% over 1 month, statistically the same as semaglutide dosed twice daily. Simulations indicated the microsphere-semaglutide would permit once-monthly administration in humans. The microsphere-semaglutide conjugate described here should be suitable for once-monthly dosing in humans, and the same approach should enable conversion of other lipidated peptides from once-weekly to once-monthly administration.
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