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
Structure for Voclosporin (DB11693)
- 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
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- Contraindications & Blackbox Warnings
Contraindications & Blackbox WarningsWith our commercial data, access important information on dangerous risks, contraindications, and adverse effects.Our Blackbox Warnings cover Risks, Contraindications, and Adverse Effects- 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
Target Actions Organism ACalcineurin subunit B type 1 inhibitorHumans ACalcineurin subunit B type 2 inhibitorHumans ACalcium signal-modulating cyclophilin ligand binderHumans - 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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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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Voclosporin can be increased when it is combined with Abametapir. Abatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Voclosporin. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Voclosporin. Abiraterone The metabolism of Voclosporin can be decreased when combined with Abiraterone. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Voclosporin. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Voclosporin. Afatinib The serum concentration of Afatinib can be increased when it is combined with Voclosporin. Aldesleukin The risk or severity of adverse effects can be increased when Aldesleukin is combined with Voclosporin. Alefacept The risk or severity of adverse effects can be increased when Alefacept is combined with Voclosporin. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Voclosporin. 
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- 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
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- Lupkynis (Aurinia Pharmaceuticals Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Lupkynis Capsule 7.9 mg/1 Oral Aurinia Pharma U.S., Inc. 2021-01-22 Not applicable US 
Categories
- ATC Codes
- L04AD03 — Voclosporin
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Antineoplastic and Immunomodulating Agents
- Calcineurin Inhibitor Immunosuppressant
- Calcineurin Inhibitors
- Cyclosporins
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Immunosuppressive Agents
- Organic Anion Transporting Polypeptide 1B1 Inhibitors
- Organic Anion Transporting Polypeptide 1B3 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Peptides
- Peptides, Cyclic
- 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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- Aurinia Pharmaceuticals Press Release: FDA Approves Aurinia Pharmaceuticals Lupkynis [Link]
- FDA Approved Products: LUPKYNIS (voclosporin) capsules, for oral use [Link]
- Toronto Research Chemicals MSDS: Voclosporin [Link]
- EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
- Aurinia Pharmaceuticals press release: Aurinia Completes Voclosporin Drug-Drug Interaction Study Demonstrating No Clinically Significant Interaction With Mycophenolate Mofetil [Link]
- External Links
- PubChem Compound
- 6918486
- PubChem Substance
- 347828058
- ChemSpider
- 5293683
- ChEBI
- 135957
- Wikipedia
- Voclosporin
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Nephritis, Lupus 1 3 Completed Treatment Anterior Uveitis (AU) / Panuveitis 1 3 Completed Treatment Chorioretinitis / Panuveitis / Uveitis, Intermediate 2 3 Completed Treatment Nephritis, Lupus 1 3 Completed Treatment Noninfectious Uveitis 1 3 Completed Treatment Psoriasis 3 3 Withdrawn Prevention Kidney Transplantation 1 2 Completed Treatment Dry Eyes 1 2 Completed Treatment Kidney Diseases 1 2 Completed Treatment Nephritis, Lupus 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 7.9 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7332472 No 2002-10-17 2022-10-17 US US10286036 No 2017-12-07 2037-12-07 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) >129 https://www.scbt.com/p/voclosporin-d4-515814-01-4-unlabeled water solubility less than 0.1 g/L https://d1io3yog0oux5.cloudfront.net/auriniapharma/files/pages/lupkynis-prescribing-information/FPI-0011+Approved+USPI++MG.pdf logP 8.6 http://www.chemspider.com/Chemical-Structure.5293683.html pKa 13.32 ± 0.70 https://www.chemicalbook.com/ChemicalProductProperty_DE_CB42496083.htm - Predicted Properties
Property Value Source logP 3.78 ChemAxon pKa (Strongest Acidic) 11.83 ChemAxon pKa (Strongest Basic) -2.4 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 12 ChemAxon Hydrogen Donor Count 5 ChemAxon Polar Surface Area 278.8 Å2 ChemAxon Rotatable Bond Count 16 ChemAxon Refractivity 331.79 m3·mol-1 ChemAxon Polarizability 133.94 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 0 ChemAxon Rule of Five No 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
- 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
- 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
- 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
- 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. [Article]
- 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. [Article]
- EMA Assessment Report: Luveniq (voclosporin) oral capsules [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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
Drug created on October 20, 2016 20:40 / Updated on May 21, 2021 10:22