Comparison of AMG 416 and cinacalcet in rodent models of uremia

BMC Nephrology

Randolph M Johnson⁷  Felix Karim⁷  Dirk B Mendel⁵  Derek Maclean⁷  Qun Yin⁸  Jin Dong³  Eiketsu Sho¹  Julie Janes⁴  Shawn T Alexander⁷  Amos Baruch⁶  Sarah Walter² 

[1] Present address: Kunming Biomedical, Kunming, China;Present address: Labrys Biologics, San Mateo, CA, USA;Present address: MedImmune, Hayward, CA, USA;Present address: Calithera Biosciences, South San Francisco, CA, USA;Present address: MedImmune, Gaithersburg, MD, USA;Present address: Genentech, South San Francisco, CA, USA;Amgen Inc, 1120 Veterans Blvd., South San Francisco, CA 94080, USA;Present address: Sutro Biopharma, South San Francisco, CA, USA

关键词: AMG 416;    Uremic rat model;    Chronic kidney disease (CKD);    Secondary hyperparathyroidism (SHPT);    Calcium-sensing receptor;   

Others  :  1082681
DOI  :  10.1186/1471-2369-15-81

 received in 2013-12-03, accepted in 2014-05-01,  发布年份 2014

【 摘 要 】

Background

AMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis.

Methods

AMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the “1K1C” model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively).

Results

Administration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals.

Conclusions

As a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.

【 授权许可】

   
2014 Walter et al.; licensee BioMed Central Ltd.

【 图 表 】

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