Characterization of Structure and Function of ZS-9, a K+ Selective Ion Trap

Abstract

Hyperkalemia, a condition in which serum potassium ions (K+) exceed 5.0 mmol/L, is a common electrolyte disorder associated with substantial morbidity. Current methods of managing hyperkalemia, including organic polymer resins such as sodium polystyrene sulfonate (SPS), are poorly tolerated and/or not effective. Sodium zirconium cyclosilicate (ZS-9) is under clinical development as an orally administered, non-absorbed, novel, inorganic microporous zirconium silicate compound that selectively removes excess K+ in vivo. The development, structure and ion exchange properties of ZS-9 and its hypothesized mechanism of action are described. Based on calculation of the interatomic distances between the atoms forming the ZS-9 micropores, the size of the pore opening was determined to be ∼3 Å (∼diameter of unhydrated K+). Unlike nonspecific organic polymer resins like SPS, the ZS-9 K+ exchange capacity (KEC) was unaffected by the presence of calcium (Ca2+) or magnesium ions (Mg2+) and showed>25-fold selectivity for K+ over either Ca2+ or Mg2+. Conversely, the selectivity of SPS for K+ was only 0.2–0.3 times its selectivity for Ca2+ or Mg2+in mixed ionic media. It is hypothesized that the high K+ specificity of ZS-9 is attributable to the chemical composition and diameter of the micropores, which possibly act in an analogous manner to the selectivity filter utilized by physiologic K+ channels. This hypothesized mechanism of action is supported by the multi-ion exchange studies. The effect of pH on the KEC of ZS-9 was tested in different media buffered to mimic different portions of the human gastrointestinal tract. Rapid K+ uptake was observed within 5 minutes - mainly in the simulated small intestinal and large intestinal fluids, an effect that was sustained for up to 1 hour. If approved, ZS-9 will represent a novel, first-in-class therapy for hyperkalemia with improved capacity, selectivity, and speed for entrapping K+ when compared to currently available options.

Potassium and Its Discontents

“…ZS-9 has a microporous framework structure and exhibits .25-fold selectivity for potassium over Ca 2+ or Mg 2+ . 83 Unlike SPS, ZS-9 does not swell within the gastrointestinal tract.…”

Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer

“…First it must be noted that the amount of the counter ion sodium in sodium zirconium cyclosilicate is substantial. The drug is reported to contain less than~8% sodium by total weight [66]. Therefore the approximate sodium content of a 10 g dose of sodium zirconium cyclosilicate, the dose tested in clinical trials, is~800 mg (35 mEq) sodium.…”

Pharmacotherapy for comorbidities in chronic heart failure: a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia

“…In short, ZS-9 is an orally administered and sorbitol-free potassium trap, which binds potassium (in exchange for sodium) in a highly selective way in the gastrointestinal tract (mainly duodenum) [109]. Three randomized, placebo-controlled phase-2 and -3 trials focused on the effectivity and safety of ZS-9 in a broad range of hyperkalemic subjects [110][111][112].…”