Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl

Abstract

Calcimimetic compounds, which activate the parathyroid cell Ca 2ϩ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC 50 ϭ 51 nM) in the presence of 0.5 mM extracellular Ca 2ϩ elicited increases in [Ca 2ϩ ] i in a dose-and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca 2ϩ , cinacalcet HCl (IC 50 ϭ 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC 50 ϭ 34 nM) produced a concentrationdependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca 2ϩ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

Experience with Cinacalcet for Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease Stage III and IV

“…14,15 Type-II CMs are compounds that bind to regions within the membrane-spanning domain and differently from type-I CMs they are dependent on extracellular calcium. 16 NPS-568 was the first type-II CM to be clinically tested 14 and Cinacalcet (Cc) was the first compound to be clinically used to treat dialysis patients with SHPT. Cc decreased iPTH levels and the Ca × P-product independently of concomitant additional vitamin-D therapy 17 and also reduced the need for parathyroid surgery (PTx).…”

Cinacalcet HCl, an Oral Calcimimetic Agent for the Treatment of Secondary Hyperparathyroidism in Hemodialysis and Peritoneal Dialysis

“…The calcium-sensing receptor located on the surface of chief cells in the parathyroid gland is the principal regulator of PTH secretion and therefore is an ideal target for therapies to treat secondary HPT (15)(16)(17). Calcimimetics are positive allosteric modulators of the calcium-sensing receptor that increase its sensitivity to extracellular calcium by lowering the threshold for activation by extracellular calcium ions (16 -18).…”

Intermittent Dosing of Cinacalcet is also Effective in Treating Secondary Hyperparathyroidism in Hemodialysis Patients

“…A daily dosing of cinacalcet effectively controls PTH values in dialysis dependent patients with SHPT not managed with traditional therapy [8]. There is plenty of clinical evidence to support the effectiveness of cinacalcet in this situation.…”