Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules

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