Abstract 509: Thermodynamic Energy Stability and In Vitro Potassium Exchange by ZS-9, a Novel Selective Cation Trap for Treatment of Hyperkalemia
Hyperkalemia is associated with significant mortality and often leads to dose reduction or cessation of RAAS inhibitors, a drug class with proven cardio- and reno-protective effects. The only approved hyperkalemia therapy in the US is a nonselective organic resin sodium polystyrene sulfonate (SPS), which is associated with Na+ loading, potentially worsening fluid retention, and hypertension. ZS-9 is an insoluble, nonsystemic inorganic cation exchanger that preferentially entraps K+ over other monovalent (eg, Na+) or divalent (Ca2+, Mg2+) cations in the GI tract. ZS-9 has a lattice structure that provides high K+ selectivity, analogous to the physiologic selectivity filters in in vivo K+ channels. Here we compared in vitro K+ exchange capacity (KEC) for ZS-9 and SPS and performed thermodynamic stability modeling for various cations (K+, Na+, Ca2+, Mg2+) within the ZS-9 lattice structure.
For KEC assessments, ZS-9 or SPS were added to a solution containing K+, Ca2+ and Mg2+. After equilibration, binding of each ion was quantified. Selectivity ratios were calculated as [K+]/([Ca2+]+[Mg2+]). The predicted energies for different cation forms of ZS-9 (ie, Na-ZS-9, K-ZS-9, Ca-ZS-9 and Mg-ZS-9), in addition to alkali and alkaline earth oxides from models, was used to estimate cation exchange energies in ZS-9. All energies were computed relative to the Na+ form of ZS-9 (“reference state”).
ZS-9 with K+ was calculated to be more thermodynamically stable than ZS-9 with Na+, Ca2+, or Mg2+, with the K+ form of ZS-9 estimated to be 20 kcal/mol more stable than the Na+ form. Preference for K+ was confirmed in vitro. Exchange capacities of ZS-9 for Ca2+ or Mg2+ were below the LLOQ (0.05 mEq/g). At a 1:1:1 ratio mixture of K+:Ca2+:Mg2+, KEC was 0.3 mEq/g for SPS vs. 2.7 mEq/g for ZS-9, indicating that ZS-9 has ≥25-fold increased selectivity for K+ vs Ca2+ or Mg2+. Selectivity of SPS for K+ was 0.2-fold that of the divalent cations.
In the presence of K+, Ca2+, and Mg2+, ZS-9 appeared to be highly selective for K+, whereas SPS was more selective for Ca2+, consistent with earlier reports. In addition, ZS-9’s capacity for K+ was ~9-fold that of SPS. If approved, ZS-9 may represent a novel first-in-class treatment for hyperkalemia with improved selectivity and capacity for K+.
Author Disclosures: B. Singh: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; ZS Pharma, Keryx, Concert, Amgen, La Jolla Pharma, Questcor. D. Speaker (includes speakers bureau, symposia, and expert witness); Modest; Questcor. A. Yang: G. Consultant/Advisory Board; Significant; ZS Pharma. M. Nuttall: A. Employment; Significant; ZS Pharma. F. Ownership Interest (includes any stock, stock option, partnership, membership or other equity position in an entity regardless of the form of the entity, or any option or right to acquire such position, and any rights in any patent or other intellectu; Modest; ZS Pharma. J. Low: G. Consultant/Advisory Board; Significant; ZS Pharma. H.S. Rasmussen: A. Employment; Significant; ZS Pharma. F. Ownership Interest (includes any stock, stock option, partnership, membership or other equity position in an entity regardless of the form of the entity, or any option or right to acquire such position, and any rights in any patent or other intellectu; Significant; ZS Pharma.
- © 2014 by American Heart Association, Inc.