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

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 (Ca(2+)) or magnesium ions (Mg(2+)) and showed>25-fold selectivity for K(+) over either Ca(2+) or Mg(2+). Conversely, the selectivity of SPS for K(+) was only 0.2–0.3 times its selectivity for Ca(2+) or Mg(2+)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.