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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
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
Adverseeffects
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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.
DrugInteraction
AmprenavirSodium zirconium cyclosilicate can cause a decrease in the absorption of Amprenavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
AsunaprevirSodium zirconium cyclosilicate can cause a decrease in the absorption of Asunaprevir resulting in a reduced serum concentration and potentially a decrease in efficacy.
AtazanavirSodium zirconium cyclosilicate can cause a decrease in the absorption of Atazanavir resulting in a reduced serum concentration and potentially a decrease in efficacy.
BisacodylThe therapeutic efficacy of Bisacodyl can be decreased when used in combination with Sodium zirconium cyclosilicate.
BosutinibSodium zirconium cyclosilicate can cause a decrease in the absorption of Bosutinib resulting in a reduced serum concentration and potentially a decrease in efficacy.
CaptoprilSodium zirconium cyclosilicate can cause a decrease in the absorption of Captopril resulting in a reduced serum concentration and potentially a decrease in efficacy.
CefditorenThe serum concentration of Cefditoren can be decreased when it is combined with Sodium zirconium cyclosilicate.
CefuroximeThe serum concentration of Cefuroxime can be decreased when it is combined with Sodium zirconium cyclosilicate.
CysteamineThe bioavailability of Cysteamine can be decreased when combined with Sodium zirconium cyclosilicate.
Dabigatran etexilateSodium zirconium cyclosilicate can cause a decrease in the absorption of Dabigatran etexilate resulting in a reduced serum concentration and potentially a decrease in efficacy.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LokelmaPowder, for suspension10 g/10gOralAstraZeneca Pharmaceuticals LP2018-09-04Not applicableUS flag
LokelmaPowder, for suspension5 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension10 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension5 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension5 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension10 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension5 g/5gOralAstraZeneca Pharmaceuticals LP2018-09-04Not applicableUS flag
LokelmaPowder, for suspension10 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension5 gOralAstra Zeneca Ab2020-12-16Not applicableEU flag
LokelmaPowder, for suspension10 g / sachetOralAstra Zeneca2019-10-17Not applicableCanada flag

Categories

ATC Codes
V03AE10 — Sodium zirconium cyclosilicate
Drug Categories
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]
KEGG Drug
D10727
RxNav
2047628
Wikipedia
Sodium_zirconium_cyclosilicate
FDA label
Download (374 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentAcute Hyperkalemia / Oral Potassium Binders1
4RecruitingTreatmentHearth Failure With Reduced Ejection Fraction (HFrEF) / Hyperkalemia1
4RecruitingTreatmentHyperkalemia1
4RecruitingTreatmentType 2 Diabetes Mellitus With Kidney Complications1
3CompletedSupportive CareHyperkalemia4
3CompletedTreatmentHyperkalemia2
3Not Yet RecruitingTreatmentACE Inhibitor Induced Hyperkalaemia / Chronic Kidney Disease (CKD) / Hearth Failure With Reduced Ejection Fraction (HFrEF) / Hyperkalemia / Mineralocorticoid Resistant Hyperkalemia1
3Not Yet RecruitingTreatmentHyperkalemia / Renal Insufficiency,Chronic1
3RecruitingTreatmentChronic Kidney Disease (CKD) / Hyperkalemia / Metabolic Acidosis1
3RecruitingTreatmentHyperkalemia4

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder, for suspensionOral10 g / sachet
Powder, for suspensionOral10 g/10g
Powder, for suspensionOral10 g
Powder, for suspensionOral5 g / sachet
Powder, for suspensionOral5 g/5g
Powder, for suspensionOral5 G
SuspensionOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9592253No2017-03-142035-10-14US flag
US8808750No2014-08-192032-02-10US flag
US9844567No2017-12-192032-02-10US flag
US9861658No2018-01-092032-02-10US flag
US6332985No2001-12-252019-03-29US flag
US8877255No2014-11-042033-10-22US flag
US8802152No2014-08-122032-04-19US flag
US9913860No2018-03-132033-10-22US flag
US10335432No2019-07-022032-02-10US flag
US10300087No2019-05-282035-10-14US flag
US10398730No2019-09-032032-02-10US flag
US10413569No2019-09-172032-02-10US flag
US10695365No2020-06-302033-10-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-3.8ChemAxon
pKa (Strongest Acidic)6.97ChemAxon
pKa (Strongest Basic)-4.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area166.05 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity12.71 m3·mol-1ChemAxon
Polarizability12.77 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Drug created on June 05, 2018 16:19 / Updated on October 15, 2021 19:56