The 1K1C model is a severe, acute model of renal dysfunction which enables the activity of AMG 416 and cinacalcet to be investigated in the presence of the highly elevated levels of PTH and lack of kidney function typically seen in CKD-MBD patients receiving hemodialysis . Due to its acute nature, the 1K1C model is not associated with the parathyroid gland hyperplasia seen in the rat 5/6 Nx uremic model and in dialysis patients with SHPT [9, 10]. However, it is an excellent model for assessing PTH-lowering activity in the background of severe kidney dysfunction. In this study, plasma PTH levels were significantly reduced by a single dose of either AMG 416 or cinacalcet. The effect of cinacalcet on PTH was of a lesser extent and shorter duration than seen with AMG 416, which maintained PTH lowering for more than 24 hr. The prolonged suppression of plasma PTH in the 1K1C model by AMG 416 is consistent with the pharmacokinetics (PK) observed for AMG 416 in normal rats and in different uremic models . The absence of kidney function results in an extended terminal half life for AMG 416, indicating that the kidney is a major clearance organ for the peptide . In contrast, the half-life of cinacalcet is independent of kidney function , as the main route of clearance is through hepatic mechanisms . Consistent with the animal data and modeling PK studies, IV administration of AMG 416 to hemodialysis patients with SHPT resulted in dose-dependent, sustained control of PTH throughout the interdialytic period .
There are a number of endpoints that can be examined in preclinical models of SHPT such as effects on PTH, serum phosphorus and calcium levels and parathyroid gland hyperplasia. In these studies, we focused on how AMG 416 compared with an approved calcimimetic, cinacalcet, at lowering plasma PTH. Additional rodent studies document the changes to parathyroid gland biology that can take place with chronic AMG 416 treatment , and the molecule’s effects on serum phosphorus levels have been shown in the clinical setting [6, 13]. For technical reasons it was not possible to obtain data for serum phosphorus in these studies.
The dose of cinacalcet in the chronic study was chosen based upon PK exposure data in rats since the area under the curve (AUC) was comparable to CKD-MBD patients with SHPT receiving hemodialysis receiving the 60 mg dose [9, 14] and is consistent with a number of published studies using cinacalcet [9, 15]. The resulting pharmacodynamic behavior for cinacalcet in this study is also consistent with previously published results . Although treatment with both agents reduced PTH shortly after dosing (6 hr post treatment), only AMG 416 was associated with sustained PTH reductions throughout and beyond the dosing interval. Throughout the four weeks of treatment in this study, animals treated with AMG 416 maintained a consistent, lower level of plasma PTH when compared with cinacalcet or placebo groups. These longer-term effects may in part arise from reversal of abnormal parathyroid gland physiology, as observed in other studies with AMG 416 .
In addition to attenuating plasma PTH in both models, both cinacalcet and AMG 416 caused a decrease in serum calcium, in agreement with previously reported studies with cinacalcet treatment in normal and uremic rats [4, 9] as well as in dialysis patients with SHPT , and consistent with the known pharmacological action of lowering PTH with this class of therapies.. This reduction in calcium can persist beyond the PTH lowering effect. In response to reduced serum calcium, a “rebound” in PTH can occur as the body perceives a state of hypocalcemia. This is seen in Table 1 and Figure 3B, where the cinacalcet-treated animals show an increased PTH level over baseline at the 16 hour time point.