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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Sodium zirconium cyclosilicate (DB14048)

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Weight

Average: 365.452
Monoisotopic: 363.77144

Chemical Formula

Na₂O₉Si₃Zr

Synonyms

• Sodium zirconium cyclosilicate
• Sodium zirconium silicate

External IDs

• UXSI-9
• ZS
• ZS-9

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

• Hyperkalemia

Contraindications & Blackbox Warnings

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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

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

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

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.
Captopril	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Captopril resulting in a reduced serum concentration and potentially a decrease in efficacy.
Cefditoren	The serum concentration of Cefditoren can be decreased when it is combined with Sodium zirconium cyclosilicate.
Cefuroxime	The serum concentration of Cefuroxime can be decreased when it is combined with Sodium zirconium cyclosilicate.
Cysteamine	The bioavailability of Cysteamine can be decreased when combined with Sodium zirconium cyclosilicate.
Dabigatran etexilate	Sodium zirconium cyclosilicate can cause a decrease in the absorption of Dabigatran etexilate resulting in a reduced serum concentration and potentially a decrease in efficacy.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

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

Categories

ATC Codes

V03AE10 — Sodium zirconium cyclosilicate

• V03AE — Drugs for treatment of hyperkalemia and hyperphosphatemia
• V03A — ALL OTHER THERAPEUTIC PRODUCTS
• V03 — ALL OTHER THERAPEUTIC PRODUCTS
• V — VARIOUS

Drug Categories

• Acids
• Acids, Noncarboxylic
• Anions
• Compounds used in a research, industrial, or household setting
• Drugs for Treatment of Hyperkalemia and Hyperphosphatemia
• Electrolytes
• Gastric Acid Lowering Agents
• Ion Exchange Resins
• Ions
• Laboratory Chemicals
• Minerals
• Oxides
• Oxygen Compounds
• Potassium Binder
• Potassium-removing Agents
• Silicon Compounds

Classification

Not classified

Affected organisms

• Humans and other mammals

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

1. AstraZeneca: ZS-9 (sodium zirconium cyclosilicate) Phase III long-term safety and efficacy data presented at ASN Kidney Week 2017 [Link]
2. AstraZeneca: Lokelma approved in the US for the treatment of adults with hyperkalaemia [Link]
3. FDA Approved Drug Products: Lokelma (sodium zirconium cyclosilicate) for oral suspension [Link]
4. 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	Recruiting	Treatment	Acute Hyperkalemia / Oral Potassium Binders	1
4	Recruiting	Treatment	Hearth Failure With Reduced Ejection Fraction (HFrEF) / Hyperkalemia	1
4	Recruiting	Treatment	Type 2 Diabetes Mellitus With Kidney Complications	1
4	Suspended	Treatment	Hyperkalemia	1
3	Active Not Recruiting	Treatment	Hyperkalemia	1
3	Completed	Supportive Care	Hyperkalemia	4
3	Completed	Treatment	Hyperkalemia	2
3	Not Yet Recruiting	Treatment	ACE Inhibitor Induced Hyperkalaemia / Chronic Kidney Disease (CKD) / Hearth Failure With Reduced Ejection Fraction (HFrEF) / Hyperkalemia / Mineralocorticoid Resistant Hyperkalemia	1
3	Recruiting	Treatment	Chronic Kidney Disease (CKD) / Hyperkalemia / Metabolic Acidosis	1
3	Recruiting	Treatment	Hyperkalemia	3

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
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)	Region
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

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

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Targets

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Details1. Potassium

Kind

Small molecule

Organism

Humans

Pharmacological action

Yes

Actions

Binder

References

1. FDA Approved Drug Products: Lokelma (sodium zirconium cyclosilicate) for oral suspension [Link]

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Drug created at June 05, 2018 16:19 / Updated at January 19, 2022 01:13