title: 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.
authors.affiliation: ZS Pharma Inc., Coppell, Texas, United States of America.
authors.forename: Fiona
authors.initials: F
authors.lastname: Stavros
authors.affiliation: Xelay Acumen, Inc., Belmont, California, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Yang
authors.affiliation: ZS Pharma Inc., Coppell, Texas, United States of America.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Leon
authors.affiliation: ZS Pharma Inc., Coppell, Texas, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Nuttall
authors.affiliation: ZS Pharma Inc., Coppell, Texas, United States of America.
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Rasmussen
mesh_terms: D002118:Calcium / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006947:Hyperkalemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007474:Ion Exchange; D007477:Ions / Q000737:chemistry; D016062:Porosity; D011188:Potassium / Q000097:blood / Q000737:chemistry*; D017640:Silicates / Q000737:chemistry* / Q000627:therapeutic use; D012964:Sodium / Q000737:chemistry
chemical_list: D007477:Ions; D017640:Silicates; D012964:Sodium; C000597310:sodium zirconium cyclosilicate; D011188:Potassium; D002118:Calcium