Sodium zirconium cyclosilicate

Sodium zirconium cyclosilicate is a non-absorbed zirconium silicate that preferentially captures potassium in exchange for hydrogen and sodium. In vitro, sodium zirconium cyclosilicate has a high affinity for potassium ions, even in the presence of other cations such as calcium and magnesium. Sodium zirconium cyclosilicate increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, thereby lowering serum potassium levels.

In a study in healthy adult subjects, sodium zirconium cyclosilicate administered as 5 g or 10 g once daily for four days caused a dose-dependent increase in fecal potassium excretion. Corresponding dose-dependent decreases in urinary potassium excretion and serum potassium were also observed.

In patients with hyperkalemia treated with sodium zirconium cyclosilicate 10 g three times a day for up to 48 hours, reductions in serum potassium were observed one hour after initiation of therapy; serum potassium concentrations continued to decline over the 48-hour treatment period. In patients not continuing sodium zirconium cyclosilicate, potassium levels increased. Patients with higher starting serum potassium levels or receiving a higher dose have greater reductions in serum potassium.

Sodium zirconium cyclosilicate causes a small dose-dependent increase in serum bicarbonate concentrations (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 as compared with a mean increase of 0.6 mmol/L in patients treated with placebo). The clinical significance of this finding is unclear.

Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In a clinical study in patients with hyperkalemia in which zirconium concentrations were measured in the urine and blood, zirconium concentrations were similar in treated and untreated patients (i.e., either undetectable or around the lower limit of quantification of the assay). An in vivo mass balance study in rats showed that sodium zirconium cyclosilicate was recovered in the feces with no evidence of systemic absorption.

Drug Interactions

Thirty-six (36) drugs were tested to determine potential interactions with sodium zirconium cyclosilicate.

Sixteen (16) drugs tested did not show an in vitro interaction with sodium zirconium cyclosilicate (allopurinol, apixaban, aspirin, captopril, cyclosporine, digoxin, ethinyl estradiol, lisinopril, magnesium, metformin, phenytoin, prednisone, propranolol, quinapril, spironolactone and ticagrelor).

Nine (9) of the 20 drugs that showed an in vitro interaction were subsequently tested in vivo in healthy volunteers. Losartan, glipizide and levothyroxine did not show any changes in exposure when co-administered with sodium zirconium cyclosilicate. However, there was an increase in systemic exposure to weak acids such as furosemide and atorvastatin, and a decrease in systemic exposure to weak bases such as dabigatran when co-administered with sodium zirconium cyclosilicate, as shown in Figure 1. These changes are consistent with the hypothesis that sodium zirconium cyclosilicate, by elevating gastric pH, affects the systemic exposure of co-administered drugs whose solubility is pH-dependent.

Figure 1. Effects of Sodium zirconium cyclosilicate on the Pharmacokinetic Exposures of Other Orally Administered Medications: