Sodium zirconium cyclosilicate

Sodium zirconium cyclosilicate is a non-absorbed, non-polymer inorganic powder with a uniform micropore structure that preferentially captures potassium in exchange for hydrogen and sodium cations. Sodium zirconium cyclosilicate is highly selective for potassium ions, even in the presence of other cations, such as calcium and magnesium, in vitro. Sodium zirconium cyclosilicate captures potassium throughout the entire gastrointestinal (GI) tract and reduces the concentration of free potassium in the GI lumen, thereby lowering serum potassium levels and increasing faecal potassium excretion to resolve hyperkalaemia.

Sodium zirconium cyclosilicate starts reducing serum potassium concentrations as soon as 1 hour after ingestion and normokalaemia can be achieved typically within 24 to 48 hours. Sodium zirconium cyclosilicate does not affect serum calcium or magnesium concentrations, or urinary sodium excretion. There is a close correlation between starting serum potassium levels and effect size; patients with higher starting serum potassium levels have greater reductions in serum potassium. There is a reduction in urinary potassium excretion which is a consequence of a reduction in serum potassium concentration. In a study of healthy subjects given sodium zirconium cyclosilicate 5 g or 10 g once daily for four days, dose- dependent reduction in serum potassium concentration and total urinary potassium excretion were accompanied by mean increases in faecal potassium excretion. No statistically significant changes in urinary sodium excretion were observed.

There were no studies conducted to investigate the pharmacodynamics when sodium zirconium cyclosilicate is administered with or without food.

Sodium zirconium cyclosilicate has also been shown to bind ammonium in vitro and in vivo, thereby removing ammonium and increasing serum bicarbonate levels. Sodium zirconium cyclosilicate-treated patients experienced an increase of 1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 g once daily in bicarbonate compared with a mean increase of 0.6 mmol/L for those receiving placebo. In an environment where other factors affecting renin and aldosterone were not controlled, sodium zirconium cyclosilicate demonstrated a dose-independent change in mean serum aldosterone levels (range: -30% to -31%) compared with the placebo group (+14%). No consistent effect on systolic and diastolic blood pressure has been observed.

In addition, mean reductions in blood urea nitrogen (BUN) were observed in the 5 g (1.1 mg/dL) and 10 g (2.0 mg/dL) three times daily groups compared with small mean increases in the placebo (0.8 mg/dL) and low dose sodium zirconium cyclosilicate (0.3 mg/dL) groups.

Absorption

Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In addition, clinical trials have shown it not to be systemically absorbed. An in vivo mass balance study in rats showed that sodium zirconium cyclosilicate was recovered in the faeces with no evidence of systemic absorption. Due to these factors and its insolubility, no in vivo or in vitro studies have been performed to examine its effect on cytochrome P450 (CYP450) enzymes or transporter activity.

Elimination

Sodium zirconium cyclosilicate is eliminated via the faeces.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.