Ramezanipour, N., Esfahani, S.H.Z., Eastell, R. orcid.org/0000-0002-0323-3366 et al. (4 more authors) (2022) Development of a hypoparathyroid male rodent model for testing delayed-clearance PTH molecules. Endocrinology, 163 (2). bqab239. ISSN 0013-7227
Abstract
Context
Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH).
Objective
The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues
Methods
Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64.
Results
Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity.
Conclusion
The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. This is an author-produced version of a paper subsequently published in Endocrinology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | PTH; hypoparathyroidism; rodent model |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number AETERNA ZENTARIS GMBH UNSPECIFIED |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 04 Jan 2022 11:09 |
Last Modified: | 28 Jun 2024 08:22 |
Status: | Published |
Publisher: | The Endocrine Society |
Refereed: | Yes |
Identification Number: | 10.1210/endocr/bqab239 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:181935 |