Sodium zirconium cyclosilicate

Identification

Summary

Sodium zirconium cyclosilicate is a potassium binder used to treat hyperkalemia.

Brand Names

Lokelma

Generic Name

Sodium zirconium cyclosilicate

DrugBank Accession Number

DB14048

Background

Sodium zirconium cyclosilicate is approved as the trade product Lokelma developed by AstraZeneca - an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension that acts as a highly selective potassium removing agent.² It is administered orally and is odorless, tasteless, and stable at room temperature.² Approval of the medication is supported by data from three double-blind, placebo-controlled trials and two open-label trials which showed that the onset of action was approximately 1.0 hour and the median time to achieving normal potassium levels in the blood was 2.2 hours, with 92% of patients achieving normal potassium levels within 48 hours following administration.² The treatment effect was maintained for up to 12 months.²

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 365.452
Monoisotopic: 363.77144
Chemical Formula: Na₂O₉Si₃Zr

Synonyms

Sodium zirconium cyclosilicate
Sodium zirconium silicate

External IDs

UXSI-9
ZS
ZS-9

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Pharmacology

Indication

Sodium zirconium cyclosilicate is a potassium binder indicated for the treatment of hyperkalemia in adult patients.^3,4

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Hyperkalemia		••••••••••••	•••••		••••••• ••• ••••••••••

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Pharmacodynamics

Sodium zirconium cyclosilicate is capable of reducing serum potassium concentrations as quickly as one hour after ingestion and normokalaemia can be achieved typically within 24 to 48 hours.^3,4 Sodium zirconium cyclosilicate does not affect serum calcium or magnesium concentrations, or urinary sodium excretion.^3,4 A close correlation is observed between starting serum potassium levels and effect size; patients with higher starting serum potassium levels have greater reductions in serum potassium.^3,4 As a consequence of the resultant reduction in serum potassium concentration, there is a reduction in urinary potassium excretion as well.^3,4 In a study of healthy subjects given sodium zirconium cyclosilicate 5 or 10 grams daily for four days, a dose-dependent reduction in serum potassium concentration and total urinary potassium excretion were accompanied by mean increases in fecal potassium excretion.^3,4 No statistically significant changes in urinary sodium excretion were observed.^3,4

Sodium zirconium cyclosilicate has also been observed to bind ammonium in vitro and in vivo, thereby removing ammonium and increasing serum bicarbonate levels.⁴ Patients treated with sodium zirconium cyclosilicate were documented as experiencing 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 the patients receiving placebo.⁴ In an environment where other factors affecting renin and aldosterone were not controlled, sodium zirconium cyclosilicate demonstrated a dose-independent reduction in mean serum aldosterone levels (range of -30% to -31%) compared with the placebo group (+14%).⁴ No consistent effect on systolic and diastolic blood pressure has yet to be observed.⁴

Moreover, 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).⁴

Mechanism of action

Hyperkalemia is a condition defined by elevated potassium levels in the blood, often caused by cardiovascular, renal, and metabolic diseases.¹ Hyperkalemia occurs in 23 to 47% of patients with chronic kidney disease and/or chronic heart failure, and may lead to cardiac arrest and death.¹

Sodium zirconium cyclosilicate is subsequently a non-absorbed, non-polymer inorganic powder with a uniform micropore structure that preferentially captures potassium in exchange for hydrogen and sodium cations.^3,4 Sodium zirconium cyclosilicate is highly selective for potassium ions, even in the presence of other cations such as calcium and magnesium, in vitro.^3,4 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 fecal potassium excretion to resolve hyperkalemia.^3,4

Target	Actions	Organism
APotassium	binder	Humans

Absorption

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not susceptible to enzymatic metabolism.⁴ Additionally, studies have shown it not to be systemically absorbed either.⁴ An in vivo mass balance study in rats showed that sodium zirconium cyclosilicate was recovered in the feces with no evidence of systemic absorption.⁴ Due to these factors and its insolubility, no in vivo or in vitro studies have thus far been performed to examine its effect on cytochrome P450 (CYP450) enzymes or transporter activity.⁴

Route of elimination

Sodium zirconium cyclosilicate is eliminated in the feces.⁴

Half-life

Not Available

Clearance

Not Available

Adverse Effects

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Toxicity

Overdose with sodium zirconium cyclosilicate could lead to hypokalemia.^3,4

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Amprenavir	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Amprenavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Asunaprevir	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Asunaprevir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Atazanavir	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Atazanavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
Bisacodyl	The therapeutic efficacy of Bisacodyl can be decreased when used in combination with Sodium zirconium cyclosilicate.
Bosutinib	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Bosutinib resulting in a reduced serum concentration and potentially a decrease in efficacy.

Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Lokelma	Powder, for suspension	5 g/5g	Oral	AstraZeneca Pharmaceuticals LP	2018-09-04	Not applicable
Lokelma	Powder, for suspension	10 g	Oral	Astra Zeneca Ab	2020-12-16	2023-02-27
Lokelma	Powder, for suspension	10 g	Oral	Astra Zeneca Ab	2020-12-16	Not applicable
Lokelma	Powder, for suspension	5 g/5g	Oral	A-S Medication Solutions	2018-09-04	Not applicable
Lokelma	Powder, for suspension	5 g / sachet	Oral	Astra Zeneca	2019-10-17	Not applicable

Chemical Identifiers

UNII: D652ZWF066
CAS number: 17141-74-1
InChI Key: ARVUQMBOTBOHPL-UHFFFAOYSA-N
InChI: InChI=1S/2Na.O9Si3.Zr/c;;1-10(2)7-11(3,4)9-12(5,6)8-10;/q2*+1;-6;
IUPAC Name: disodium 1,3,5,2,4,6-trioxatrisilinane-2,2,4,4,6,6-hexakis(olate) zirconium
SMILES: [Na+].[Na+].[Zr].[O-][Si]1([O-])O[Si]([O-])([O-])O[Si]([O-])([O-])O1

References

General References

AstraZeneca: ZS-9 (sodium zirconium cyclosilicate) Phase III long-term safety and efficacy data presented at ASN Kidney Week 2017 [Link]
AstraZeneca: Lokelma approved in the US for the treatment of adults with hyperkalaemia [Link]
FDA Approved Drug Products: Lokelma (sodium zirconium cyclosilicate) for oral suspension [Link]
EMA Sodium Zirconium Cyclosilicate Monograph [File]

External Links

KEGG Drug: D10727
RxNav: 2047628
Wikipedia: Sodium_zirconium_cyclosilicate

FDA label

Download (374 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Hearth Failure With Reduced Ejection Fraction (HFrEF) / Hyperkalemia	1
4	Recruiting	Prevention	Hyperkalemia	1
4	Recruiting	Treatment	Acute Hyperkalemia / Oral Potassium Binders	1
4	Recruiting	Treatment	Chronic Kidney Disease (CKD) / Hyperkalemia	1
4	Terminated	Treatment	Hyperkalemia	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Powder	Oral	5.000 g
Powder, for suspension	Oral	10 g / sachet
Powder, for suspension	Oral	10 g/10g
Powder, for suspension	Oral	5 g / sachet
Powder, for suspension	Oral	5 g/5g
Powder, for suspension	Oral	10 g
Powder, for suspension	Oral	5 g
Suspension	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9592253	No	2017-03-14	2035-10-14
US8808750	No	2014-08-19	2032-02-10
US9844567	No	2017-12-19	2032-02-10
US9861658	No	2018-01-09	2032-02-10
US6332985	No	2001-12-25	2019-03-29
US8877255	No	2014-11-04	2033-10-22
US8802152	No	2014-08-12	2032-04-19
US9913860	No	2018-03-13	2033-10-22
US10335432	No	2019-07-02	2032-02-10
US10300087	No	2019-05-28	2035-10-14
US10398730	No	2019-09-03	2032-02-10
US10413569	No	2019-09-17	2032-02-10
US10695365	No	2020-06-30	2033-10-22
US11406662	No	2012-02-10	2032-02-10
US11738044	No	2015-10-14	2035-10-14

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
logP	-3.8	Chemaxon
pKa (Strongest Acidic)	6.97	Chemaxon
pKa (Strongest Basic)	-4.4	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	9	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	166.05 Å²	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	12.71 m³·mol^-1	Chemaxon
Polarizability	12.77 Å³	Chemaxon
Number of Rings	1	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features