Abstract 509: Thermodynamic Energy Stability and In Vitro Potassium Exchange by ZS-9, a Novel Selective Cation Trap for Treatment of Hyperkalemia

Abstract

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 (Ca 2+ , Mg 2+ ) 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 + , Ca 2+ , Mg 2+ ) within the ZS-9 lattice structure. For KEC assessments, ZS-9 or SPS were added to a solution containing K + , Ca 2+ and Mg 2+ . After equilibration, binding of each ion was quantified. Selectivity ratios were calculated as [K + ]/([Ca 2+ ]+[Mg 2+ ]). 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 + , Ca 2+ , or Mg 2+ , 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 Ca 2+ or Mg 2+ were below the LLOQ (0.05 mEq/g). At a 1:1:1 ratio mixture of K + :Ca 2+ :Mg 2+ , 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 Ca 2+ or Mg 2+ . Selectivity of SPS for K + was 0.2-fold that of the divalent cations. In the presence of K + , Ca 2+ , and Mg 2+ , ZS-9 appeared to be highly selective for K + , whereas SPS was more selective for Ca 2+ , 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 + .