Pharmacology of Parsabiv® (etelcalcetide, ONO-5163/AMG 416), a novel allosteric modulator of the calcium-sensing receptor, for secondary hyperparathyroidism in hemodialysis patients.
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.
['Harada|Kazutsune|K|', 'Fujioka|Aiko|A|', 'Konno|Masakazu|M|', 'Inoue|Atsuto|A|', 'Yamada|Hiroyuki|H|', 'Hirota|Yasushi|Y|']
D061605:Administration, Intravenous D000494:Allosteric Regulation D000818:Animals D002118:Calcium D057809:HEK293 Cells D006801:Humans D006962:Hyperparathyroidism, Secondary D010280:Parathyroid Glands D010281:Parathyroid Hormone D010455:Peptides D051381:Rats D044169:Receptors, Calcium-Sensing D006435:Renal Dialysis
ONO-5163/AMG 416 Calcium-sensing receptor Secondary hyperparathyroidism Calcimimetic