A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient

Abstract

Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin–angiotensin–aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12–0.3 g, 24–3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/− 21.8 vs. +8.9 +/− 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium.

Chronic Hyperkalemia in Cardiorenal Patients: Risk Factors, Diagnosis, and New Treatment Options

“…It is believed that the ion channels formed by the atomic structure of ZS-9 mimic those of endogenous potassium channels. When the sodium (or hydrogen) ion dissociates from ZS-9, a negative charge and pore size of 3 Å make potassium (2.98 Å) the ideal cation for trapping [55]. ZS-9 possesses 9 times the potassium-binding capacity of SPS in vitro [54].…”

“…In 66 patients receiving RAASi therapy, the 10-g dose produced a mean reduction of –0.12 ± 0.50 mEq/L by 1 h compared to a mean increase of 0.19 ± 0.31 mEq/L with placebo ( p < 0.03). The most common adverse effects were nausea, vomiting, and urinary tract infection, with each occurring in 5% (3 of 60) of ZS-9 patients [55]. …”

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults

“…ACEi/ARB, β-blockers and potassium-sparing diuretic were used for hypertension, chronic heart failure, arrhythmia and diabetes. Hyperkalemia was defined as a serum potassium level " 5 mEq/L (21,22). The baseline potassium level was obtained at the beginning of treatment with TMP-SMX.…”

Pharmacodynamics and pharmacokinetics of sodium zirconium cyclosilicate [ZS-9] in the treatment of hyperkalemia

“…[34] Neither ZS-9 nor free zirconium is absorbed in beagle dogs, based on urinary and blood analysis. Given that ZS-9 has not shown to be systemically absorbed and that its effect on a serum pharmacodynamics marker occurs in the gut lumen, the physiological mechanisms of potassium homeostasis appear to be restored in the presence of ZS-9.…”