The Calcimimetic Agent AMG 073 Lowers Plasma Parathyroid Hormone Levels in Hemodialysis Patients with Secondary Hyperparathyroidism

Abstract

ABSTRACT. Treatment with vitamin D sterols can lower plasma parathyroid hormone (PTH) in many patients with secondary hyperparathyroidism due to end-stage renal disease, but hypercalcemia, hyperphosphatemia, or both often develop during treatment. As such, alternative therapeutic approaches to managing excess PTH secretion are needed. Calcimimetic agents directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid glands, but clinical experience with them is limited. Fifty-two hemodialysis patients with secondary hyperparathyroidism were given single orally administered doses of the calcimimetic agent AMG 073 ranging from 5 to 100 mg, or placebo. Plasma PTH levels decreased 2 h after 25-, 50-, 75-, or 100-mg doses, falling by a maximum of 43 ± 29%, 40 ± 36%, 54 ± 28%, or 55 ± 39%, respectively. Plasma PTH levels decreased in all patients given doses of ≥25 mg but did not change in those who received placebo. In patients treated with daily doses of 25 or 50 mg of AMG 073 for 8 d, plasma PTH levels declined for the first 3 to 4 d and remained below baseline values after 8 d of treatment. Serum calcium concentrations also decreased by 5 to 10% from pretreatment levels in patients given 50 mg of AMG 073 for 8 d, but values were unchanged in those who received lower doses. Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073. Thus, 8 d of treatment with AMG 073 effectively lowers plasma PTH levels and improves several disturbances in mineral metabolism that have been associated with soft tissue and vascular calcification and with adverse cardiovascular outcomes in patients with end-stage renal disease.

Relationship between Reductions in Parathyroid Hormone and Serum Phosphorus during the Management of Secondary Hyperparathyroidism with Calcimimetics in Hemodialysis Patients

“…Whereas reductions in plasma PTH after initiation of cinacalcet most likely account for the observed changes in serum phosphorus concentration re-Relationship between PTH and Phosphorus after Cinacalcet Therapy Nephron Clin Pract 2012;121:c124-c130 c129 ported here, the calcium-sensing receptor is also expressed in bone cells and intestines. A direct effect of cinacalcet to modify mineral flux into and out of bone or phosphorus absorption from the gastrointestinal tract by a PTH-independent mechanism thus cannot be excluded as a potential explanation for interval changes in serum phosphorus during treatment with cinacalcet [16] .…”

Mineral Bone Disorders in Kidney Disease Patients: The Ever-Current Topic

“…It regulates the synthesis and secretion of PTH by increasing the sensitivity of the calcium-sensing receptor (CaSR) to extracellular calcium ions [ 113 ]. It is taken orally, and it provides a rapid, dose-dependent reduction in plasma PTH levels that persists for up to 24 h after drug administration [ 114 ]. In two large phase 3, randomized, double-blind, multicentre, clinical trials involving in total 741 patients undergoing hemodialysis, a significantly higher proportion of patients receiving cinacalcet 30–180 mg/day achieved a reduction in PTH levels to < or = 250 pg/mL, compared to placebo [ 115 ].…”

Treatment of secondary hyperparathyroidism in kidney disease: what we know and do not know about use of calcimimetics and vitamin D analogs

“…In 2002, the fi rst evidence that cinacalcet lowered PTH levels emerged. 8 When cinacalcet, then known as AMG 073, or placebo was given to 30 hemodialysis (HD) patients for 8 days, treated subjects demonstrated a statistically significant improvement in PTH levels, measured as percent change from baseline. Calcium, P and Ca × P also fell, although p-values were not reported.…”