“The GLP-1 Mimetic Exenatide Potentiates Insulin Secretion in Healthy Cats”, 2011-07 (; backlinks; similar):
- Glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be effective in treating feline diabetes.
A stable exenatide analog shows favorable pharmacokinetic and pharmacodynamic effects in cats.
A hydrogel drug delivery system allows monthly subcutaneous delivery of GLP-1RAs in cats.
We propose a patient-selection protocol for treatment of diabetes in cats with a GLP-1RA.
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 ( et al 2017).
The purposes of the present study were (1) to demonstrate pharmacokinetic and pharmacodynamic similarities of the deamidation-sensitive GLP-1RA exenatide and the closely related, more stable [Gln28]exenatide and (2) 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.