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Abstract: PO0318

Upacicalcet, a Novel Non-Peptide Calcimimetic for the Treatment of Secondary Hyperparathyroidism, Has a Low Risk of Hypocalcemia

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Nishimura, Go, Sanwa Kagaku Kenkyusho, Co.,Ltd., Inabe, Mie, Japan
  • Yamaguchi, Yu, Sanwa Kagaku Kenkyusho, Co.,Ltd., Inabe, Mie, Japan
  • Goto, Moritaka, Sanwa Kagaku Kenkyusho, Co.,Ltd., Inabe, Mie, Japan
  • Honda, Daisuke, Sanwa Kagaku Kenkyusho,Co.,Ltd., Nagoya, Aichi, Japan
  • Takahashi, Naoki, Sanwa Kagaku Kenkyusho, Co.,Ltd., Inabe, Mie, Japan
Background

Calcimimetics are widely used for the treatment of secondary hyperparathyroidism (SHPT) in chronic renal failure patients. However, there are some problems with calcimimetics treatment. One of the biggest problems is hypocalcemia that leads to treatment interruption. Upacicalcet is expected to be a novel non-peptide calcimimetic that does not cause excessive hypocalcemia from the results of clinical studies. In the present study, we investigated the pharmacological characteristics of upacicalcet and effect on hypocalcemia in preclinical studies.

Methods

In vitro study was conducted using human CaSR-expressing (hCaSR+) HEK-293T cells. In in vivo study, upacicalcet was intravenously administered in a single dose to Double-Nephrectomized (Double-Nx) rats, an animal model of SHPT, and serum intact parathyroid hormone (iPTH) and Ca concentrations were measured.

Results

Upacicalcet increased the intracellular Ca2+ concentration in hCaSR+ HEK-293T cells dose-dependently. Additionally, upacicalcet shifted the EC50 value for extracellular Ca2+ to lower concentrations in a dose dependent manner. In Double-Nx rats, 0.3, 3, and 30 mg/kg of upacicalcet dose-dependently reduced the serum iPTH level at 24h and 48h after administration, and the reductions were significantly greater than that in Control (Pre; upacicalcet 0.3 mg/kg: 483±70 pg/mL vs. Control: 460±39 pg/mL, 24h; upacicalcet 0.3 mg/kg: 397±40 pg/mL vs. Control: 1306±86 pg/mL; P<0.001, 48h; upacicalcet 0.3 mg/kg: 795±91 pg/mL vs. Control: 1889±77 pg/mL; P<0.001). Upacicalcet also significantly decreased the serum Ca level dose-dependently at 24h and 48h after administration. However, interestingly, it bottomed out without getting too low even with 30 mg/kg of upacicalcet, 100-fold higher than the efficacious dose (0.3 mg/kg) (Table 1).

Conclusion

These findings suggest upacicalcet is a novel non-peptide positive allosteric modulator on human CaSR with a low risk of hypocalcemia for the patients with SHPT.