Sodium Zirconium Cyclosilicate (ZS-9): A Novel Agent for the Treatment of Hyperkalemia

Abstract

Hyperkalemia is a potentially life-threatening electrolyte abnormality that may be caused by select medications, underlying organ dysfunction, or alterations in potassium homeostasis. Treatment for this condition has remained largely unchanged since the release of sodium polystyrene sulfonate (SPS) in 1958. Despite its widespread use, the safety and efficacy of SPS remains controversial. Two novel potassium-binding resins have emerged in recent years. Patiromer was the first of these to receive U.S. Food and Drug Administration approval for the treatment of hyperkalemia in October 2015. A second potassium-binding resin, a zirconium cyclosilicate currently known as ZS-9, may provide yet another alternative to the archetypal treatment with SPS. ZS-9 is an orally administered nonabsorbed inorganic compound that selectively binds potassium ions in vivo. Two phase III multicenter, randomized, placebo-controlled, double-blind trials have evaluated ZS-9 for the treatment of acute hyperkalemia. In this review, we discuss the pharmacology, clinical efficacy, safety, and potential place in therapy of ZS-9 for the enhanced elimination of potassium in the setting of hyperkalemia.

Evidence in support of hyperkalaemia management strategies: A systematic literature review

“…SPS has been available since 1958, which precedes both the Kefauver‐Harris Drug Amendment (1962) and the European Union EC/65/65 directive (1965), requiring drugs to be both safe and efficacious to be granted marketing approval . Considering that SPS has been used for decades for non‐emergency hyperkalaemia treatment, it is striking that robust evidence in support of its efficacy is lacking . For example, the only RCT identified in this SLR comparing SPS to placebo may have been biased because of differences in population baseline characteristics, and underpowered because of a very small sample size of 33 patients; a considerably smaller number than the 754 patients in ZS‐003 or the 90 patients in ZS‐002 …”

“…A robust and clinically meaningful ITC of ZS to SPS/CPS was infeasible because of heterogeneity between studies (including study design, patient populations and time points for study end‐points), as well as very small sample sizes in the SPS/CPS trials, and use of dosing regimens different to those in the SmPC for SPS/CPS. This lack of rigorous evidence has been highlighted by a number of experts in the field, stressing the need for well‐designed, robust RCTs of established treatments to inform clinical guidelines for the management of hyperkalaemia.…”

“…[94][95][96] Considering that SPS has been used for decades for non-emergency hyperkalaemia treatment, it is striking that robust evidence in support of its efficacy is lacking. 97 For example, the only RCT identified in this SLR comparing SPS to placebo may have been biased because of differences in population baseline characteristics, and underpowered because of a very small sample size of 33 patients; 31 a considerably smaller number than the 754 patients in ZS-003 or the 90 patients in ZS-002. 28 Because of their side effect profile and poor tolerability, SPS and CPS are generally only used in a non-emergency correction setting, whereas long-term strategies are currently limited to K + -lowering diet or discontinuation of hyperkalaemia-inducing medication.…”

Pharmacology of new treatments for hyperkalaemia: patiromer and sodium zirconium cyclosilicate

“…A report by the EMA (25 January 2018-EMA/93250/2018-Committee for Medicinal Products for Human Use) stated that SZC is indicated for the treatment of hyperkalaemia in adult patients. Pharmacological properties of SZC have been described in detail elsewhere 22 and are summarized in Table 2 . Briefly, this agent is an inorganic cation exchange crystalline compound that allows a thermodynamically favourable catching of potassium ions 23 .…”

Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice

“…24 Sodium zirconium cyclosilicate (ZS-9) is another agent being developed as a treatment for hyperkalemia. 25 …”