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


Schneider, E L; Reid, R; Parkes, D G; Lutz, Thomas; Ashley, G W; Santi, D V (2020). A once-monthly GLP-1 receptor agonist for treatment of diabetic cats. Domestic animal endocrinology, 70:106373.

Abstract

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, [Gln$^{28}$]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 [Gln$^{28}$]exenatide and b) to develop a long-acting GLP-1RA in cats. The results show that exenatide and [Gln$^{28}$]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 [Gln$^{28}$]exenatide has superior bioavailability-93% for [Gln$^{28}$]exenatide vs 52% for exenatide. The results also show that exenatide and [Gln$^{28}$]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-[Gln$^{28}$]exenatide conjugate containing an appropriate self-cleaving linker in the cat provides plasma [Gln$^{28}$]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 [Gln$^{28}$]exenatide as a treatment for feline diabetes, and the microsphere-[Gln$^{28}$]exenatide conjugate is quite suitable for once-monthly subcutaneous administration of the peptide in the cat.

Abstract

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, [Gln$^{28}$]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 [Gln$^{28}$]exenatide and b) to develop a long-acting GLP-1RA in cats. The results show that exenatide and [Gln$^{28}$]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 [Gln$^{28}$]exenatide has superior bioavailability-93% for [Gln$^{28}$]exenatide vs 52% for exenatide. The results also show that exenatide and [Gln$^{28}$]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-[Gln$^{28}$]exenatide conjugate containing an appropriate self-cleaving linker in the cat provides plasma [Gln$^{28}$]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 [Gln$^{28}$]exenatide as a treatment for feline diabetes, and the microsphere-[Gln$^{28}$]exenatide conjugate is quite suitable for once-monthly subcutaneous administration of the peptide in the cat.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Health Sciences > Food Animals
Life Sciences > Animal Science and Zoology
Life Sciences > Endocrinology
Uncontrolled Keywords:Exenatide; Feline diabetes; GLP1-RA; Half-life extension; Pharmacokinetics.
Language:English
Date:1 January 2020
Deposited On:16 Dec 2019 12:35
Last Modified:29 Jul 2020 12:02
Publisher:Elsevier
ISSN:0739-7240
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.domaniend.2019.07.001
PubMed ID:31479925

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