title: Comparison of AMG 416 and cinacalcet in rodent models of uremia.
abstract: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Walter
authors.forename: Amos
authors.initials: A
authors.lastname: Baruch
authors.forename: Shawn T
authors.initials: ST
authors.lastname: Alexander
authors.forename: Julie
authors.initials: J
authors.lastname: Janes
authors.forename: Eiketsu
authors.initials: E
authors.lastname: Sho
authors.forename: Jin
authors.initials: J
authors.lastname: Dong
authors.forename: Qun
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Amgen Inc, 1120 Veterans Blvd,, South San Francisco, CA 94080, USA. dmaclean@amgen.com.
authors.forename: Derek
authors.initials: D
authors.lastname: Maclean
authors.forename: Dirk B
authors.initials: DB
authors.lastname: Mendel
authors.forename: Felix
authors.initials: F
authors.lastname: Karim
authors.forename: Randolph M
authors.initials: RM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D057966:Calcimimetic Agents / Q000008:administration & dosage*; D000069449:Cinacalcet; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects; D016896:Treatment Outcome; D014511:Uremia / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D057966:Calcimimetic Agents; D009281:Naphthalenes; D010455:Peptides; D044169:Receptors, Calcium-Sensing; C583569:etelcalcetide hydrochloride; D000069449:Cinacalcet