Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate Binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% (P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.