Ziconotide

Identification

Name
Ziconotide
Accession Number
DB06283
Description

Ziconotide (also known as SNX-111) is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds.7,18 Other such peptides, collectively termed conotoxins, exist, and some have shown efficacy in binding specific subsets of calcium channels; ziconotide is used in part because it can be synthesized without loss of proper bond formation or structural elements.5,6 Ziconotide is used to manage severe chronic pain refractory to other methods, through its ability to inhibit N-type calcium channels involved in nociceptive signalling.5,7,8,9,12,14,18

Ziconotide was granted FDA approval on December 28, 2004 for marketing by TerSera therapeutics LLC. under the name Prialt.18 To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA.7

Type
Small Molecule
Groups
Approved
Synonyms
  • Ziconotida
  • Ziconotide
External IDs
  • SNX-111

Pharmacology

Indication

Ziconotide is indicated for the management of severe chronic pain in patients refractory to other treatments, and for whom intrathecal therapy is warranted.18

Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ziconotide inhibits N-type calcium channels involved in nociceptive signalling, primarily in the dorsal horn of the spinal cord.5,7,8,9,12,14,18 Although binding is reversible, careful dosing is required to ensure therapeutic effects while minimizing adverse effects, and ziconotide has been described as possessing a narrow therapeutic window.13,18 Patients taking ziconontide may experience cognitive and neuropsychiatric symptoms, reduced levels of consciousness, and elevated serum creatine kinase levels. In addition, ziconotide may increase the risk of infection, including serious cases of meningitis. Patients who withdraw from opiates for ziconotide initiation are advised to taper off the dose.18

Mechanism of action

Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord.8,14 Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling and include the N-type (Cav2.2) heteromultimeric high-voltage type calcium channels.10 Chronic pain conditions, including inflammatory and neuropathic pain, often involve the aberrant upregulation of VGCC activity through various cellular mechanisms, which can lead to allodynia and hyperalgesia.14

Specifically, N-type channel activation in lightly myelinated Aδ- and C-fibres is known to mediate the release of neurotransmitters substance P (SP), calcitonin gene-related peptide (CGRP), and glutamate, which influence downstream neural activation and pain perception.8,14,15,16,17 In addition, SP and CGRP induce inflammation, potentially exacerbating pre-existing inflammatory chronic pain.14

Ziconotide belongs to the ω-conotoxin class of neurotoxic peptides derived from the cone snail Conus magus which are capable of inhibiting N-type VGCCs.4,5,7,9,18 Although the exact mechanism is yet to be elucidated, it is thought that ω-conotoxins function through direct occlusion of the ion pore to prevent calcium translocation across the membrane.9 Additional studies involving expression of chimeric subunits and molecular modelling suggest that insertion of the ziconotide Met12 residue into a hydrophobic pocket formed by Ile300, Phe302, and Leu305 of Cav2.2 increases binding and may be associated with toxic adverse effects.11

TargetActionsOrganism
AVoltage-dependent N-type calcium channel subunit alpha-1B
inhibitor
Humans
NVoltage-dependent P/Q-type calcium channel subunit alpha-1A
inhibitor
Humans
Absorption

Ziconotide administered intrathecally over one hour in doses between 1 and 10 mcg produced calculated AUC values between 83.6-608 ng*h/mL and Cmax between 16.4-132 ng/mL; these values are approximately dose-proportional. Given the intrathecal administration and low membrane permeability due to its size, ziconotide is expected to remain primarily in the CSF; plasma levels, where detected, remain constant up to nine months following administration.18

Volume of distribution

In patients administered 1-10 mcg intrathecal ziconotide over one hour, the apparent volume of distribution was calculated as 155 ± 263 mL; this value is roughly equivalent to the expected CSF volume.18 Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an apparent volume of distribution of 30,460 ± 6366 mL.18

Protein binding

Ziconotide is roughly 50% bound to human plasma proteins.18

Metabolism

Ziconotide is expected to be processed by various peptidases upon entering systemic circulation; no detailed information on ziconotide metabolism has been reported.18

Route of elimination

A small fraction of intravenous ziconotide (< 1%) is recovered in urine.18

Half-life

In patients administered 1-10 mcg intrathecal ziconotide over one hour, the elimination half-life was calculated as 4.6 ± 0.9 hr. Although intravenous administration is not indicated, intravenous administration of between 0.3-10 mcg/kg/day ziconotide resulted in an elimination half-life of 1.3 ± 0.3 hr.18

Clearance

Ziconotide CSF clearance is 0.38 ± 0.56 mL/min while plasma clearance is 270 ± 44 mL/min.18

Adverse Effects
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Toxicity

Symptoms of overdose include neurological effects such as ataxia, nystagmus, stupor, sedation, speech difficulties, dizziness, nausea, and vomiting, and may also cause other effects such as hypotension; overdose is not associated with respiratory depression. In case of overdose, symptom-related supportive care up to and including hospitalization is recommended. Ziconotide has no known antidote, but the withdrawal of ziconotide generally allows patients to clear the drug and recover within 24 hours. As ziconotide does not bind to opiate receptors, opioid antagonists are not effective at ameliorating overdose effects.18

Affected organisms
  • Humans and other mammals
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
AcarboseThe risk or severity of hypoglycemia can be increased when Ziconotide is combined with Acarbose.
AcebutololThe risk or severity of bradycardia can be increased when Ziconotide is combined with Acebutolol.
AcetazolamideThe risk or severity of CNS depression can be increased when Acetazolamide is combined with Ziconotide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Ziconotide is combined with Acetohexamide.
AcetophenazineThe risk or severity of CNS depression can be increased when Acetophenazine is combined with Ziconotide.
AcetyldigitoxinZiconotide may increase the arrhythmogenic activities of Acetyldigitoxin.
AclidiniumZiconotide may increase the central nervous system depressant (CNS depressant) activities of Aclidinium.
AdenosineZiconotide may increase the arrhythmogenic activities of Adenosine.
AgomelatineThe risk or severity of adverse effects can be increased when Ziconotide is combined with Agomelatine.
AjmalineAjmaline may increase the arrhythmogenic activities of Ziconotide.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
  • Avoid excessive or chronic alcohol consumption. Ingesting alcohol may increase the CNS depressive effects of ziconotide.

Products

Product Ingredients
IngredientUNIICASInChI Key
Ziconotide acetateT2I226K69M914454-03-8Not applicable
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PrialtInjection, solution100 ug/1mLIntrathecalTersera Therapeutics Llc2018-10-15Not applicableUS flag
PrialtInjection, solution25 μg/mlIntrathecalEisai Limited2005-02-21Not applicableEU flag
PrialtInjection, solution25 ug/1mLIntrathecalElan Pharmaceuticals2004-12-282012-01-01US flag
PrialtInjection, solution100 ug/1mLIntrathecalJazz Pharmaceuticals, Inc.2004-12-282022-09-30US flag
PrialtInjection, solution100 μg/mlIntrathecalEisai Limited2005-02-21Not applicableEU flag
PrialtInjection, solution100 ug/1mLIntrathecalElan Pharmaceuticals2004-12-282013-04-01US flag
PrialtInjection, solution25 ug/1mLIntrathecalTersera Therapeutics Llc2018-10-15Not applicableUS flag
PrialtInjection, solution100 μg/mlIntrathecalEisai Limited2005-02-21Not applicableEU flag
PrialtInjection, solution25 ug/1mLIntrathecalJazz Pharmaceuticals, Inc.2004-12-282022-07-31US flag
PrialtInjection, solution100 ug/1mLIntrathecalTersera Therapeutics Llc2018-10-15Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
N02BG08 — Ziconotide
Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
7I64C51O16
CAS number
107452-89-1
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

References

Synthesis Reference

Avi Tovi, Chaim Eidelman, Shimon Shushan, Shai Elster, Alon Hagi, Alexander Ivchenko, Gabriel-Marcus Butilca, Gil Zaoui, Eleonora Alterman, Leah Bar-Oz, Tehila Gadi. "Methods for the production of peptide having a c-terminal amide." Patent WO2006119388A2, issued November 09, 2006.

General References
  1. Skov MJ, Beck JC, de Kater AW, Shopp GM: Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class. Int J Toxicol. 2007 Sep-Oct;26(5):411-21. [PubMed:17963128]
  2. Miljanich GP: Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004 Dec;11(23):3029-40. [PubMed:15578997]
  3. McGivern JG: Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr Dis Treat. 2007 Feb;3(1):69-85. [PubMed:19300539]
  4. Olivera BM, Gray WR, Zeikus R, McIntosh JM, Varga J, Rivier J, de Santos V, Cruz LJ: Peptide neurotoxins from fish-hunting cone snails. Science. 1985 Dec 20;230(4732):1338-43. doi: 10.1126/science.4071055. [PubMed:4071055]
  5. Olivera BM, Cruz LJ, de Santos V, LeCheminant GW, Griffin D, Zeikus R, McIntosh JM, Galyean R, Varga J, Gray WR, et al.: Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry. 1987 Apr 21;26(8):2086-90. doi: 10.1021/bi00382a004. [PubMed:2441741]
  6. Valentino K, Newcomb R, Gadbois T, Singh T, Bowersox S, Bitner S, Justice A, Yamashiro D, Hoffman BB, Ciaranello R, et al.: A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7894-7. doi: 10.1073/pnas.90.16.7894. [PubMed:8102803]
  7. Bourinet E, Zamponi GW: Block of voltage-gated calcium channels by peptide toxins. Neuropharmacology. 2017 Dec;127:109-115. doi: 10.1016/j.neuropharm.2016.10.016. Epub 2016 Oct 15. [PubMed:27756538]
  8. Park J, Luo ZD: Calcium channel functions in pain processing. Channels (Austin). 2010 Nov-Dec;4(6):510-7. doi: 10.4161/chan.4.6.12869. Epub 2010 Nov 1. [PubMed:21150297]
  9. Patel R, Montagut-Bordas C, Dickenson AH: Calcium channel modulation as a target in chronic pain control. Br J Pharmacol. 2018 Jun;175(12):2173-2184. doi: 10.1111/bph.13789. Epub 2017 Apr 26. [PubMed:28320042]
  10. Simms BA, Zamponi GW: Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014 Apr 2;82(1):24-45. doi: 10.1016/j.neuron.2014.03.016. [PubMed:24698266]
  11. Wang F, Yan Z, Liu Z, Wang S, Wu Q, Yu S, Ding J, Dai Q: Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA. Neuropharmacology. 2016 Feb;101:137-45. doi: 10.1016/j.neuropharm.2015.08.047. Epub 2015 Sep 4. [PubMed:26344359]
  12. Deer TR, Pope JE, Hanes MC, McDowell GC: Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options. Pain Med. 2019 Apr 1;20(4):784-798. doi: 10.1093/pm/pny132. [PubMed:30137539]
  13. Sanford M: Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs. 2013 Nov;27(11):989-1002. doi: 10.1007/s40263-013-0107-5. [PubMed:23999971]
  14. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW: Calcium-permeable ion channels in pain signaling. Physiol Rev. 2014 Jan;94(1):81-140. doi: 10.1152/physrev.00023.2013. [PubMed:24382884]
  15. Evans AR, Nicol GD, Vasko MR: Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res. 1996 Mar 18;712(2):265-73. doi: 10.1016/0006-8993(95)01447-0. [PubMed:8814901]
  16. Maggi CA, Tramontana M, Cecconi R, Santicioli P: Neurochemical evidence for the involvement of N-type calcium channels in transmitter secretion from peripheral endings of sensory nerves in guinea pigs. Neurosci Lett. 1990 Jul 3;114(2):203-6. doi: 10.1016/0304-3940(90)90072-h. [PubMed:1697665]
  17. Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ: The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain. 2002 Mar;96(1-2):119-27. doi: 10.1016/s0304-3959(01)00436-5. [PubMed:11932068]
  18. FDA Approved Drug Products: Prialt (ziconotide) solution [Link]
KEGG Drug
D06363
PubChem Substance
347910345
RxNav
68503
ChEMBL
CHEMBL2103752
Wikipedia
Ziconotide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailablePeripheral neuropathy1
4RecruitingTreatmentPain, Neuropathic1
4WithdrawnTreatmentPainful Myelopathy / Painful Neuropathy1
3CompletedTreatmentPain2
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Malignancies / Pain1
2Unknown StatusTreatmentMalignancies / Pain / Pain, Intractable / Pain, Neuropathic1
Not AvailableCompletedNot AvailablePatients With Severe Chronic Pain1
Not AvailableNot Yet RecruitingNot AvailableIntrathecal / Refractory Pains1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntrathecal100 MICROGRAMMI/ML
Injection, solutionIntrathecal100 ug/1mL
Injection, solutionIntrathecal100 μg/ml
Injection, solutionIntrathecal25 ug/1mL
Injection, solutionIntrathecal25 μg/ml
Injection, solutionIntrathecal25 MICROGRAMMI/ML
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5859186No1999-01-122011-12-30US flag
US5364842No1994-11-152016-12-30US flag
US8653033No2014-02-182024-10-01US flag
US8765680No2014-07-012024-10-01US flag
US9707270No2017-07-182024-10-01US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
Not Available
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1B
Uniprot ID
Q00975
Uniprot Name
Voltage-dependent N-type calcium channel subunit alpha-1B
Molecular Weight
262493.84 Da
References
  1. Olivera BM, Cruz LJ, de Santos V, LeCheminant GW, Griffin D, Zeikus R, McIntosh JM, Galyean R, Varga J, Gray WR, et al.: Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry. 1987 Apr 21;26(8):2086-90. doi: 10.1021/bi00382a004. [PubMed:2441741]
  2. Valentino K, Newcomb R, Gadbois T, Singh T, Bowersox S, Bitner S, Justice A, Yamashiro D, Hoffman BB, Ciaranello R, et al.: A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7894-7. doi: 10.1073/pnas.90.16.7894. [PubMed:8102803]
  3. Bourinet E, Zamponi GW: Block of voltage-gated calcium channels by peptide toxins. Neuropharmacology. 2017 Dec;127:109-115. doi: 10.1016/j.neuropharm.2016.10.016. Epub 2016 Oct 15. [PubMed:27756538]
  4. Park J, Luo ZD: Calcium channel functions in pain processing. Channels (Austin). 2010 Nov-Dec;4(6):510-7. doi: 10.4161/chan.4.6.12869. Epub 2010 Nov 1. [PubMed:21150297]
  5. Patel R, Montagut-Bordas C, Dickenson AH: Calcium channel modulation as a target in chronic pain control. Br J Pharmacol. 2018 Jun;175(12):2173-2184. doi: 10.1111/bph.13789. Epub 2017 Apr 26. [PubMed:28320042]
  6. Wang F, Yan Z, Liu Z, Wang S, Wu Q, Yu S, Ding J, Dai Q: Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA. Neuropharmacology. 2016 Feb;101:137-45. doi: 10.1016/j.neuropharm.2015.08.047. Epub 2015 Sep 4. [PubMed:26344359]
  7. Bourinet E, Altier C, Hildebrand ME, Trang T, Salter MW, Zamponi GW: Calcium-permeable ion channels in pain signaling. Physiol Rev. 2014 Jan;94(1):81-140. doi: 10.1152/physrev.00023.2013. [PubMed:24382884]
  8. FDA Approved Drug Products: Prialt (ziconotide) solution [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
Curator comments
The reported inhibition was low, even at relatively high peptide concentrations; this interaction is unlikely to play a substantial role in vivo.
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1A
Uniprot ID
O00555
Uniprot Name
Voltage-dependent P/Q-type calcium channel subunit alpha-1A
Molecular Weight
282362.39 Da
References
  1. Wang F, Yan Z, Liu Z, Wang S, Wu Q, Yu S, Ding J, Dai Q: Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA. Neuropharmacology. 2016 Feb;101:137-45. doi: 10.1016/j.neuropharm.2015.08.047. Epub 2015 Sep 4. [PubMed:26344359]

Drug created on March 19, 2008 10:21 / Updated on June 12, 2020 10:52

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