Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice

Abstract

Introduction: Hyperkalemia is a common complication in patients with heart failure or chronic kidney disease, particularly those who are taking inhibitors of the renin-angiotensin-aldosterone system. RDX7675, the calcium salt of a reengineered polystyrene sulfonate-based resin, is a potassium binder that is being investigated as a novel treatment for hyperkalemia. This study evaluated the pharmacodynamic effects of RDX7675 in mice, compared to 2 current treatments, sodium polystyrene sulfonate (SPS) and patiromer.

Methods: Seven groups of 8 male CD-1 mice were given either standard chow (controls) or standard chow containing 4.0% or 6.6% active moiety of RDX7675, patiromer, or SPS for 72 hours. Stool and urine were collected over the final 24 hours of treatment for ion excretion analyses.

Results: RDX7675 increased stool potassium (mean 24-hour excretion: 4.0%, 9.19 mg; 6.6%, 18.11 mg; both P < .0001) compared with controls (4.47 mg) and decreased urinary potassium (mean 24-hour excretion: 4.0%, 12.05 mg, P < .001; 6.6%, 6.68 mg, P < .0001; vs controls, 20.38 mg). The potassium-binding capacity of RDX7675 (stool potassium/gram of resin: 4.0%, 1.14 mEq/g; 6.6%, 1.32 mEq/g) was greater (all P < .0001) than for patiromer (4.0%, 0.63 mEq/g; 6.6%, 0.48 mEq/g) or SPS (4.0%, 0.73 mEq/g; 6.6% 0.55 mEq/g). RDX7675 and patiromer decreased urinary sodium (mean 24-hour excretion: 0.07-1.38 mg; all P < .001) compared to controls (5.01 mg). In contrast, SPS increased urinary sodium excretion (4.0%, 13.31 mg; 6.6%, 17.60 mg; both P < .0001) compared to controls.

Conclusions: RDX7675 reduced intestinal potassium absorption and had a greater potassium-binding capacity than patiromer or SPS in mice. The calcium-based resins RDX7675 and patiromer reduced intestinal sodium absorption, unlike sodium-based SPS. These results support further studies in humans to confirm the potential of RDX7675 for the treatment of patients with hyperkalemia.

Keywords: RDX7675; hyperkalemia; patiromer; potassium; sodium polystyrene sulfonate.

Figure 1.

Effects of potassium-binder treatment on mean 24-hour potassium excretion in mice. Total stool and urinary excretion (A, C). Stool and urinary excretion normalized to intake (out/in; B, D). Potassium-binding capacity calculated for total resin and active moiety, respectively (E, F). Data shown are mean + standard error of mean. All n = 8. Symbols denote significance versus corresponding comparator (1-way ANOVA followed by Tukey test): 1 symbol, P < .05; 2 symbols, P < .01; 3 symbols, P < .001; 4 symbols, P < .0001. ⁁control, *SPS 4.0%, ^†SPS 6.6%, ^‡patiromer 4.0%, ^§patiromer 6.6%, and ^∼RDX7675 4.0%. ANOVA indicates analysis of variance; SPS, sodium polystyrene sulfonate.

Figure 2.

Effects of potassium-binder treatment on mean 24-hour excretion of sodium (A, B), calcium (C, D), and phosphorus (E, F) in mice. Data shown are mean + standard error of mean. All n = 8. Symbols denote significance versus corresponding comparator (1-way ANOVA followed by Tukey test): 1 symbol, P < .05; 2 symbols, P < .01; 3 symbols, P < .001; 4 symbols, P < .0001. ⁁control, *SPS 4.0%, ^†SPS 6.6%, ^‡patiromer 4.0%, ^§patiromer 6.6%, and ^∼RDX7675 4.0%. ANOVA indicates analysis of variance; SPS, sodium polystyrene sulfonate.

Figure 3.

Effects of potassium-binder treatment on mean 24-hour excretion of sodium (A, B), calcium (C, D), and phosphorus (E, F) in mice, normalized to intake (out/in). Data shown are mean + standard error of mean. All n = 8. Symbols denote significance versus corresponding comparator (1-way ANOVA followed by Tukey test): 1 symbol, P < .05; 2 symbols, P < .01; 3 symbols, P < .001; 4 symbols, P < .0001. ⁁control, *SPS 4.0%, ^†SPS 6.6%, ^‡patiromer 4.0%, ^§patiromer 6.6%, and ^∼RDX7675 4.0%. ANOVA indicates analysis of variance; SPS, sodium polystyrene sulfonate.

Figure 4.

Effects of potassium-binder treatment on mean 24-hour stool wet weight (A) and fluid content (B) in mice. Data shown are mean + standard error of mean. All n = 8. Symbols denote significance versus corresponding comparator (1-way ANOVA followed by Tukey test): 1 symbol, P < .05; 2 symbols, P < .01. ⁁control, *SPS 4.0%, ^†SPS 6.6%, ^‡patiromer 4.0%, and ^§patiromer 6.6%. ANOVA indicates analysis of variance; SPS, sodium polystyrene sulfonate.