A once-monthly GLP-1 receptor agonist for treatment of diabetic cats

艾塞那肽 药理学 药代动力学 医学 兴奋剂 内科学 受体 内分泌学 2型糖尿病 糖尿病
作者
Eric L. Schneider,Ralph Reid,David G. Parkes,Thomas Lutz,Gary W. Ashley,Daniel V. Santi
出处
期刊:Domestic Animal Endocrinology [Elsevier]
卷期号:70: 106373-106373 被引量:8
标识
DOI:10.1016/j.domaniend.2019.07.001
摘要

There is growing evidence that peptidic glucagon-like peptide-1 receptor agonists (GLP-1RA), such as exenatide, may provide useful therapeutic options for treatment of feline diabetes. However, because such drugs are administered subcutaneously, it is desirable that they be long-acting and not require frequent injections. We have developed a chemically controlled delivery system to support half-life extension of peptidic therapeutics. Here, the peptide is covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection of the microspheres, the peptide is slowly released from the depot to the systemic circulation. Using this technology, we developed a delivery system that supports once-monthly administration of a stable exenatide analog, [Gln28]exenatide, in rodents (Schneider, et al, ACS Chem Biol 12, 2107 to 2116, 2017). The purposes of the present study were a) to demonstrate pharmacokinetic and pharmacodynamic similarities of the deamidation-sensitive GLP-1RA exenatide and the closely related, more stable [Gln28]exenatide and b) to develop a long-acting GLP-1RA in cats. The results show that exenatide and [Gln28]exenatide injected intravenously or subcutaneously at 10 μg/kg have nearly identical pharmacokinetics in the cat—both having elimination half-lives of ∼40 min—but subcutaneously administered [Gln28]exenatide has superior bioavailability—93% for [Gln28]exenatide vs 52% for exenatide. The results also show that exenatide and [Gln28]exenatide have similar insulinotropic activities in the cat during a high-dose intravenous glucose tolerance test; they increased the area under the curve (AUC) for insulin to a similar extent but had no effect on glucose AUC. Finally, subcutaneous injection of a microsphere-[Gln28]exenatide conjugate containing an appropriate self-cleaving linker in the cat provides plasma [Gln28]exenatide with a half-life of about 40 d vs 40 min with the injected free peptide. Hence, the large body of information available for exenatide can be used to facilitate clinical development of [Gln28]exenatide as a treatment for feline diabetes, and the microsphere-[Gln28]exenatide conjugate is quite suitable for once-monthly subcutaneous administration of the peptide in the cat.
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