Voclosporin

Identification

Summary

Voclosporin is a calcineurin inhibitor for the treatment of lupus nephritis (LN) in patients diagnosed with systemic lupus erythematosus (SLE).

Brand Names
Lupkynis
Generic Name
Voclosporin
DrugBank Accession Number
DB11693
Background

Lupus nephritis (LN) is a type of glomerulonephritis occurring in patients with systemic lupus erythematosus (SLE). LN is a significant cause of renal failure, morbidity, and death in patients with SLE. Within 10 years of being diagnosed with SLE, 5-20% of those suffering from LN develop end-stage kidney disease, a fatal condition. Early and accurate intervention for LN is important in improving clinical outcomes.2

Voclosporin, marketed as Lupkynis, is a calcineurin-inhibitor immunosuppressant for the treatment of LN.6 This cyclosporine A analog was approved by the FDA on January 22, 2021 following promising results in clinical trials. Early intervention with voclosporin coupled with a kidney response is believed to prevent irreversible damage to the kidney and lead to better long-term clinical outcomes for patients with LN.5 Voclosporin has demonstrated a more stable pharmacokinetic and pharmacodynamic relationship than cyclosporine, a higher potency than cyclosporine, and an improved metabolic profile when compared to older calcineurin inhibitors.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 1214.646
Monoisotopic: 1213.841368058
Chemical Formula
C63H111N11O12
Synonyms
  • Voclosporin
External IDs
  • ISA-247
  • ISA247
  • ISATX-247
  • ISATX247
  • LX-211
  • LX211
  • R 1524

Pharmacology

Indication

Voclosporin is used in combination with a background immunosuppressive regimen for the treatment of lupus nephritis. Safety has not been established in combination with cyclophosphamide.6

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Voclosporin inhibits calcineurin, leading to the inhibition of T cell activation by blocking the transcription of early inflammatory cytokines. This reduces inflammation in the kidney, treating lupus nephritis and preventing permanent renal damage.7

Mechanism of action

Through the inhibition of calcineurin, voclosporin blocks IL-2 expression and T-cell mediated immune responses, stabilizing podocytes in the kidneys.9

Voclospoprin is a cyclosporine A analog. It is structurally similar to cyclosporine A (CsA) with the exception of an amino acid modification in one region. This modification changes the binding of voclosporin to calcineurin. Cyclosporine inhibitors reversibly inhibit T-lymphocytes. They also inhibit lymphokine production and release. Cyclosporine A exerts its inhibitory effects on T-lymphocytes by binding to cyclophilin. A cyclophilin-cyclosporine complex is formed, leading to the inhibition of calcium- and calmodulin-dependent serine-threonine phosphatase activity of calcineurin. Along with calcineurin inhibition, the inhibition of many transcription factors necessary for the induction of various cytokine genes such as IL-2, IFN-γ, IL-4 and GM-CSF occurs. This, in turn, reduces inflammation, treating renal glomerulonephritis associated with systemic lupus erythematosus.3,8

TargetActionsOrganism
ACalcineurin subunit B type 1
inhibitor
Humans
ACalcineurin subunit B type 2
inhibitor
Humans
ACalcium signal-modulating cyclophilin ligand
binder
Humans
Absorption

When administered on an empty stomach, the median Tmax of voclosporin is 1.5 hours, but can range from 1-4 hours.6 The AUC is estimated at 7693.6 ng/mL*h and the Cmax is estimated at 955.5 ng/mL.1

Volume of distribution

The apparent volume of distribution of voclosporin is 2,154 L. Voclosporin distributes extensively into red blood cells; distribution between whole blood and plasma is dependent on concentration and temperature.6

Protein binding

The protein binding of voclosporin is approximately 97%.6

Metabolism

Voclosporin is mainly metabolized by the CYP3A4 hepatic cytochrome enzyme. Pharmacologic activity is mainly attributed to the parent molecule. A major metabolite has been detected in human whole blood, representing 16.7% of total exposure; this metabolite is about 8-fold less potent than the parent drug, voclosporin.6,8

Route of elimination

Voclosporin is eliminated in the urine and feces, with about 88% detected in the feces and about 2% detected in the urine.8

Half-life

The average terminal half-life of voclosporin is about 30 hours (24.9 to 36.5 hours).6

Clearance

The mean apparent steady-state clearance of voclosporin is 63.6 L/h.6 Hepatic and renal impairment significantly reduce the clearance of voclosporin.4

Adverse Effects
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Toxicity

LD50 information for voclosporin is not readily available.

Accidental overdose with voclosporin has been reported with; symptoms of an overdose may include headache, nausea and vomiting, infections, tachycardia, urticaria, lethargy, and tremor. An increase in blood urea nitrogen, serum creatinine, and alanine aminotransferase levels is also possible. There is no known antidote to an overdose with voclosporin. If an overdose occurs, supportive and symptomatic treatment should be initiated, in addition to discontinuation of voclosporin. Assessment of blood urea nitrogen, serum creatinine, eGFR and alanine aminotransferase levels is recommended. Prescribing information suggests contacting a poison center or medical toxicologist for the management of an overdose with voclosporin.6

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
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Voclosporin.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Voclosporin.
AbirateroneThe metabolism of Voclosporin can be decreased when combined with Abiraterone.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Voclosporin.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Voclosporin.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Voclosporin.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Voclosporin.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Voclosporin.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Voclosporin.
AltretamineThe risk or severity of adverse effects can be increased when Altretamine is combined with Voclosporin.
Interactions
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Food Interactions
  • Avoid grapefruit products. Avoid food or drink containing grapefruit when taking voclosporin, as it may decrease metabolism and increase exposure to this drug.
  • Take on an empty stomach. Take on an empty stomach, either 1 hour before or 2 hours after a meal and as close to 12 hours between doses as possible.

Products

Products
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International/Other Brands
Lupkynis (Aurinia Pharmaceuticals Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LupkynisCapsule7.9 mg/1OralAurinia Pharma U.S., Inc.2021-01-22Not applicableUS flag

Categories

ATC Codes
L04AD03 — Voclosporin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cyclosporins. These are cyclic depsipeptides containing the cyclosporin backbone.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Peptoid-peptide hybrids
Direct Parent
Cyclosporins
Alternative Parents
Oligopeptides / Macrolactams / Alpha amino acids and derivatives / Tertiary carboxylic acid amides / Secondary carboxylic acid amides / Secondary alcohols / Lactams / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds
show 3 more
Substituents
Alcohol / Aliphatic heteromonocyclic compound / Alpha-amino acid or derivatives / Alpha-oligopeptide / Azacycle / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Cyclosporin-backbone / Hydrocarbon derivative
show 12 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
2PN063X6B1
CAS number
515814-01-4
InChI Key
BICRTLVBTLFLRD-PTWUADNWSA-N
InChI
InChI=1S/C63H111N11O12/c1-25-27-28-29-41(15)53(76)52-57(80)66-44(26-2)59(82)68(18)34-49(75)69(19)45(30-35(3)4)56(79)67-50(39(11)12)62(85)70(20)46(31-36(5)6)55(78)64-42(16)54(77)65-43(17)58(81)71(21)47(32-37(7)8)60(83)72(22)48(33-38(9)10)61(84)73(23)51(40(13)14)63(86)74(52)24/h25,27-28,35-48,50-53,76H,1,26,29-34H2,2-24H3,(H,64,78)(H,65,77)(H,66,80)(H,67,79)/b28-27+/t41-,42+,43-,44+,45+,46+,47+,48+,50+,51+,52+,53-/m1/s1
IUPAC Name
(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methylhepta-4,6-dien-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-bis(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecone
SMILES
[H][C@@]1([C@H](O)[C@H](C)C\C=C\C=C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](CC)NC1=O)C(C)C

References

General References
  1. Li Y, Palmisano M, Sun D, Zhou S: Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies. Clin Pharmacol. 2020 Jul 1;12:83-96. doi: 10.2147/CPAA.S255789. eCollection 2020. [PubMed:32669879]
  2. Anders HJ, Saxena R, Zhao MH, Parodis I, Salmon JE, Mohan C: Lupus nephritis. Nat Rev Dis Primers. 2020 Jan 23;6(1):7. doi: 10.1038/s41572-019-0141-9. [PubMed:31974366]
  3. Schultz C: Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis. 2013 May 5;5:5-10. doi: 10.4137/OED.S7995. Print 2013. [PubMed:23700374]
  4. Ling SY, Huizinga RB, Mayo PR, Freitag DG, Aspeslet LJ, Foster RT: Pharmacokinetics of voclosporin in renal impairment and hepatic impairment. J Clin Pharmacol. 2013 Dec;53(12):1303-12. doi: 10.1002/jcph.166. Epub 2013 Oct 8. [PubMed:23996158]
  5. Aurinia Pharmaceuticals Press Release: FDA Approves Aurinia Pharmaceuticals Lupkynis [Link]
  6. FDA Approved Products: LUPKYNIS (voclosporin) capsules, for oral use [Link]
  7. Toronto Research Chemicals MSDS: Voclosporin [Link]
  8. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
  9. Aurinia Pharmaceuticals press release: Aurinia Completes Voclosporin Drug-Drug Interaction Study Demonstrating No Clinically Significant Interaction With Mycophenolate Mofetil [Link]
PubChem Compound
6918486
PubChem Substance
347828058
ChemSpider
5293683
ChEBI
135957
Wikipedia
Voclosporin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentNephritis, Lupus1
3CompletedTreatmentAnterior Uveitis (AU) / Panuveitis1
3CompletedTreatmentChorioretinitis / Panuveitis / Uveitis, Intermediate2
3CompletedTreatmentNephritis, Lupus1
3CompletedTreatmentNoninfectious Uveitis1
3CompletedTreatmentPsoriasis3
3WithdrawnPreventionTransplantation, Renal1
2CompletedTreatmentDry Eyes1
2CompletedTreatmentKidney Diseases1
2CompletedTreatmentNephritis, Lupus2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral7.9 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7332472No2002-10-172022-10-17US flag
US10286036No2017-12-072037-12-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)>129https://www.scbt.com/p/voclosporin-d4-515814-01-4-unlabeled
water solubilityless than 0.1 g/L https://d1io3yog0oux5.cloudfront.net/auriniapharma/files/pages/lupkynis-prescribing-information/FPI-0011+Approved+USPI++MG.pdf
logP8.6http://www.chemspider.com/Chemical-Structure.5293683.html
pKa13.32 ± 0.70https://www.chemicalbook.com/ChemicalProductProperty_DE_CB42496083.htm
Predicted Properties
PropertyValueSource
logP3.78ChemAxon
pKa (Strongest Acidic)11.83ChemAxon
pKa (Strongest Basic)-2.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area278.8 Å2ChemAxon
Rotatable Bond Count16ChemAxon
Refractivity331.79 m3·mol-1ChemAxon
Polarizability133.94 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Protein domain specific binding
Specific Function
Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity.
Gene Name
PPP3R1
Uniprot ID
P63098
Uniprot Name
Calcineurin subunit B type 1
Molecular Weight
19299.785 Da
References
  1. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Calcium ion binding
Specific Function
Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity (By similarity).
Gene Name
PPP3R2
Uniprot ID
Q96LZ3
Uniprot Name
Calcineurin subunit B type 2
Molecular Weight
19533.065 Da
References
  1. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
  2. FDA Approved Products: LUPKYNIS (voclosporin) capsules, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Not Available
Specific Function
Likely involved in the mobilization of calcium as a result of the TCR/CD3 complex interaction. Binds to cyclophilin B.
Gene Name
CAMLG
Uniprot ID
P49069
Uniprot Name
Calcium signal-modulating cyclophilin ligand
Molecular Weight
32952.255 Da
References
  1. Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M: Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011 Feb;67(Pt 2):119-23. doi: 10.1107/S0907444910051905. Epub 2011 Jan 15. [PubMed:21245533]
  2. Schultz C: Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis. 2013 May 5;5:5-10. doi: 10.4137/OED.S7995. Print 2013. [PubMed:23700374]
  3. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Products: LUPKYNIS (voclosporin) capsules, for oral use [Link]
  2. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
  2. FDA Approved Products: LUPKYNIS (voclosporin) capsules, for oral use [Link]

Drug created on October 20, 2016 20:40 / Updated on February 21, 2021 18:53