Voclosporin

Voclosporin
Names
Preferred 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-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
Other names
VCS, ISA247, Luveniq
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
PubChem CID
UNII
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
    Key: BICRTLVBTLFLRD-PTWUADNWSA-N
  • InChI=1/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
    Key: BICRTLVBTLFLRD-PTWUADNWBK
SMILES
  • O=C1N(C)[C@H](C(=O)N[C@H](C(=O)N(C)CC(=O)N(C)[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N(C)[C@H](C(=O)N(C)[C@H]1C(C)C)CC(C)C)CC(C)C)C)C)C)CC(C)C)C(C)C)CC(C)C)CC)[C@H](O)[C@H](C)C\C=C\C=C
Properties
Chemical formula
 C63H111N11O12
Molar mass 1214.646 g·mol−1
Pharmacology
L04AD03 (WHO)
By mouth
Legal status
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Voclosporin
Clinical data
Trade namesLupkynis
License data
Identifiers
DrugBank
KEGG

Voclosporin, sold under the brand name Lupkynis, is a calcineurin inhibitor used as an immunosuppressant medication for the treatment of lupus nephritis.[1][3]

It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.[4]

It was approved for medical use in the United States in January 2021,[5][6][7] and in the European Union in September 2022.[2]

Medical uses

Lupus nephritis is a common form of glomerular nephritis occurring in patients with systemic lupus nephritis. Lupus nephritis commonly leads patients to chronic kidney failure and therefore places an emphasis on early intervention for improving treatment outcomes. Early intervention with voclosporin in combination with kidney response is believed to lead to more positive clinical outcomes for lupus nephritis patients.[8] Thus, voclosporin is used in combination with background immunosuppressive regimen for the treatment of lupus nephritis. Safety has not been established in combination with cyclophosphamide.[8]

Contraindications

Patients who are breastfeeding or plan to breastfeed should not take this medication as it may cause fetal harm.[1] Voclosporin is not recomnended in patients with a baseline eGFR less than or equal to 45 ml/min/1.73 m2 unless benefits exceeds risk. Dose should be reduced if the drug is used within this population as well as for patients who are hepatically impaired.[1] Avoid the use of live attenuated vaccines when patients are on this medication.[1] Avoid co-administration of voclosporin and other moderate to strong CYP3A4 inhibitors and if needed then reduce the dose of voclosporin. Dosages of PgP-substrate drugs should be reduced if co-administered with voclosporin.[8]

Adverse effects

Voclosporin has a boxed warning for malignancies and serious infections. Patients taking Voclosporin along with other immunosuppressants have an increased risk for developing malignancies and serious infections that may lead to hospitalization or death.[1] The most common adverse reactions of voclosporin were (>3%), glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain(upper), dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue. tremor, acute kidney injury, and decreased appetite.

Pharmacology

Voclosporin is a cyclosporin A analog, similar to cyclosporin A with modifications on an amino acid within one region that allows the drug to bind to Calcineurin.[8] Voclosporin inhibits calcineurin, which then blocks the production of IL-2 and T-cell mediated immune responses. As a result of the calcineurin inhibition, podocytes (cells within the kidneys) are stabilized while inflammation is reduced. Reduction of inflammation within the kidneys prevents further renal damage.[8]

Pharmacokinetics

When administered on an empty stomach, the median Tmax of voclosporin is 1.5 hours.[8] The AUC is estimated to be 7693 ng/mL and the Cmax is estimated at 955 ng/mL.[8] The volume of distribution is approximately 2,154 L and distributes within the red blood cells. The distribution between the plasma and whole blood is affected by temperature and concentration.[8] The protein binding of voclosporin is 97%. The average terminal half-life of voclosporin is 63.6 L/h. The drug is mainly metabolized by the CYP3A4 hepatic cytochrome enzyme.[8] Pharmacologic activity is mainly attributed to the parent molecule itself, with the major metabolite being 8-fold less potent than the parent drug.[8]

History

Voclosporin was discovered by Isotechnika in the 1990s.[9] Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013. In January 2021, Aurinia Pharmaceuticals received approval from the Food & Drug Administration to sell the drug Lupkynis.[6][5]

Society and culture

On 21 July 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Lupkynis, intended for the treatment of lupus nephritis.[2][10] The applicant for this medicinal product is Otsuka Pharmaceutical Netherlands B.V.[10] Voclosporin was approved for medical use in the European Union in September 2022.[2]

References
  1. "Lupkynis- voclosporin capsule". DailyMed. Archived from the original on 30 July 2022. Retrieved 13 September 2021.
  2. "Lupkynis EPAR". European Medicines Agency. 19 July 2022. Archived from the original on 22 September 2022. Retrieved 21 September 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. Sin FE, Isenberg D (October 2018). "An evaluation of voclosporin for the treatment of lupus nephritis" (PDF). Expert Opinion on Pharmacotherapy. 19 (14): 1613–1621. doi:10.1080/14656566.2018.1516751. PMID 30207816. S2CID 52196375. Archived (PDF) from the original on 13 March 2020. Retrieved 10 March 2021.
  4. "What is voclosporin?". Isotechnika. Archived from the original on 29 September 2012. Retrieved 19 October 2012.
  5. "Drug Approval Package: Lupkynis". U.S. Food and Drug Administration (FDA). 24 February 2021. Archived from the original on 15 September 2021. Retrieved 14 September 2021.
  6. "Drug Trials Snapshot: Lupkynis". U.S. Food and Drug Administration (FDA). 22 January 2021. Archived from the original on 11 February 2021. Retrieved 12 February 2021.
  7. "FDA Approves Aurinia Pharmaceuticals' Lupkynis (voclosporin) for Adult Patients with Active Lupus Nephritis". Aurinia Pharmaceuticals Inc. (Press release). 22 January 2021. Archived from the original on 25 January 2021. Retrieved 25 January 2021.
  8. "Voclosporin". go.drugbank.com. Archived from the original on 16 April 2022. Retrieved 16 April 2022.
  9. U.S. Patent 6,605,593
  10. "Lupkynis: Pending EC decision". European Medicines Agency. 21 July 2022. Archived from the original on 28 July 2022. Retrieved 30 July 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  • "Voclosporin". Drug Information Portal. U.S. National Library of Medicine.
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