Pharmacology of Parsabiv® (etelcalcetide, ONO-5163/AMG 416), a novel allosteric modulator of the calcium-sensing receptor, for secondary hyperparathyroidism in hemodialysis patients.

Abstract

Etelcalcetide hydrochloride (Parsabiv®, ONO-5163/AMG 416) is an allosteric modulator of the calcium (Ca)-sensing receptor that was originally produced by KAI Pharmaceuticals Inc. (now Amgen Inc.). It has recently been approved as the first intravenous calcimimetic agent for secondary hyperparathyroidism (SHPT) in many countries. Etelcalcetide is an intravenous injectable drug that can be administered and eliminated through the dialysis circuit in chronic kidney disease patients. In the present study, we evaluated the in vitro pharmacological profile and in vivo parathyroid hormone (PTH)- and Ca-lowering activities of etelcalcetide in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT. Etelcalcetide increased the intracellular Ca concentration in HEK-293T cells expressing human Ca-sensing receptor with an EC50 value (95% confidence interval) of 0.53 μM (0.28-1.0 μM) and suppressed PTH secretion from rat parathyroid gland cells with 0.36 μM (0.24-0.54 μM) by activating Ca-sensing receptor. The specificity of etelcalcetide was evaluated by examining its ability to stimulate or inhibit radioligand binding to a panel of 34 off-target proteins. There were no significant changes in the presence of 10 μM etelcalcetide. Furthermore, in a rat 5/6 nephrectomy model of chronic renal insufficiency with SHPT, single intravenous administration of etelcalcetide at 0.3, 1.0, and 3.0 mg/kg decreased plasma PTH and serum Ca levels. Taken together, the present findings identify etelcalcetide as a calcimimetic with potent PTH- and Ca-lowering effects via Ca-sensing receptor agonist activity.

• Authors: Kazutsune Harada, Aiko Fujioka, Masakazu Konno, Atsuto Inoue, Hiroyuki Yamada, Yasushi Hirota
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 842 Pg. 139-145 (Jan 05 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30342948 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Parathyroid Hormone
• Peptides
• Receptors, Calcium-Sensing
• etelcalcetide hydrochloride
• Calcium

Topics

• Administration, Intravenous
• Allosteric Regulation (drug effects)
• Animals
• Calcium (blood)
• HEK293 Cells
• Humans
• Hyperparathyroidism, Secondary (blood, drug therapy, metabolism)
• Parathyroid Glands (drug effects, metabolism)
• Parathyroid Hormone (blood)
• Peptides (administration & dosage, pharmacology, therapeutic use)
• Rats
• Receptors, Calcium-Sensing (chemistry, metabolism)
• Renal Dialysis