Sodium zirconium cyclosilicate increases serum bicarbonate concentrations among patients with hyperkalaemia: exploratory analyses from three randomized, multi-dose, placebo-controlled trials

Abstract

Background Sodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)]. Methods In all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia. Results Significant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate. Conclusions SZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy.

Phase I Study of the Pharmacodynamics and Safety of Sodium Zirconium Cyclosilicate in Healthy Chinese Adults

“…These observations are consistent with those from phase III SZC studies of patients with hyperkalemia. 29 The observed increase in serum bicarbonate is likely due to SZC binding of gastrointestinal ammonium, while decreases in serum urea are associated with SZC effects on serum bicarbonate. 29 Indeed, these findings in healthy volunteers are of note as maintaining serum bicarbonate ≥22 mmol/L is a major goal for the treatment of CKD.…”

Zirconium cyclosilicate: An oral sorbent for potassium, four decades in the making

“…11 Several Phase III studies confirmed the mild increase in serum bicarbonate levels with SZC, and a later path analysis performed in a metaanalysis showed that the probable cause for this increase in bicarbonate was ammonium absorption by SZC in the gut. 12 The Phase III studies also confirmed that SZC decreased serum urea levels in a dose-dependent manner, with the highest doses causing a decrease of 15%-20%. 13,14 In end-stage renal disease (ESRD) patients oral SZC can effectively decrease high pre-dialysis potassium levels in patients on 3/week dialysis.…”

“…Probably the pinnacle of my career was my 2013 presentation on Phase II and III trials during the “Late Breaking Clinical Trials” session at the American Society of Nephrology (ASN) 11 . Several Phase III studies confirmed the mild increase in serum bicarbonate levels with SZC, and a later path analysis performed in a meta‐analysis showed that the probable cause for this increase in bicarbonate was ammonium absorption by SZC in the gut 12 . The Phase III studies also confirmed that SZC decreased serum urea levels in a dose‐dependent manner, with the highest doses causing a decrease of 15%–20% 13,14 .…”

Dose effect analysis of sodium zirconium cyclosilicate in hemodialysis patients

“…The impact of SZC dose on serum bicarbonate was not assessed here; however, increases in serum bicarbonate levels have been shown with SZC in a dose-dependent manner in Phase 3 studies of patients with hyperkalemia. 9 Indeed, in patients on maintenance dialysis in DIALIZE, similar increases from baseline in serum bicarbonate were observed with SZC overall at Day 57 (mean [SD]: SZC +0.5 1 This observed increase in serum bicarbonate is likely due to SZC binding of gastrointestinal ammonium. The impact of dose titration in each SZC dose group and the post hoc nature of the analysis should be considered when interpreting these findings.…”