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Abstract: FR-PO499

Combination Treatment with Tenapanor and Sevelamer Synergistically Reduces Urinary Phosphate Excretion in Rats

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • King, Andrew J., Ardelyx, Fremont, California, United States
  • Kohler, Jill N., Ardelyx, Fremont, California, United States
  • Fung, Cyra, Ardelyx, Fremont, California, United States
  • Jiang, Zhengfeng, Ardelyx, Fremont, California, United States
  • Quach, Allison, Ardelyx, Fremont, California, United States
  • Kumaraswamy, Padmapriya, Ardelyx, Fremont, California, United States
  • Rosenbaum, David P., Ardelyx, Fremont, California, United States
Background

Many chronic kidney disease (CKD) patients on dialysis fail to achieve target serum phosphate (P) levels, despite treatment with available P binding agents. Tenapanor is a first-in-class, minimally absorbed small molecule NHE3 inhibitor that reduces intestinal P absorption and is under investigation as a novel treatment for hyperphosphatemia in CKD patients on dialysis. This study evaluated the effect of tenapanor and varying doses of sevelamer carbonate administered alone and in combination on urinary P excretion, an index of intestinal P absorption, in rats.

Methods

Male Sprague Dawley rats were assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided with a diet containing varying amounts of sevelamer (0-3% w/w) for 11 days. 24-hour urinary P excretion was measured over the final 4 days. The effect of the addition of tenapanor (0.3 mg/kg/day) or vehicle for 7-days on 24-hour urinary P excretion in rats (n=6/group) already on a stable dose of sevelamer (1.5% w/w) for 6 days was also assessed.

Results

In combination with tenapanor, sevelamer dose-dependently decreased urinary P excretion such that the combination effect was significantly greater than either tenapanor or the equivalent dose of sevelamer alone across all sevelamer dose levels (Figure). The BLISS statistical model of independence indicated that the drug combination interaction between tenapanor and sevelamer was synergistic. On a stable sevelamer dose (1.5% w/w) that reduced urinary P excretion by 42 ± 3% (P<0.001), the addition of tenapanor reduced residual urinary P excretion by 37 ± 6% (P<0.05).

Conclusion

The combination of tenapanor and sevelamer results in greater reductions in intestinal P absorption than when either agent is administered alone. Clinical evaluation of the potential for the combination of tenapanor and sevelamer to more effectively achieve serum P target levels in hyperphosphatemic CKD patients on dialysis is warranted.

Funding

  • Commercial Support