Voclosporin is the name of this novel semisynthetic calcineurin (CN) inhibitor (ISATX247). Using an in vitro calcineurin assay, the immunosuppressive effectiveness of vocasporin was investigated [1]. In vitro, the calcineurin inhibitor vocosporin (ISATX247) is more potent than cyclosporine [2].

All of the animals showed good tolerance to cyclosporine A (CsA) and voclosporin (ISATX247). Serious adverse effects are absent from both drugs. During the trial, all but one animal in the Voclosporin group experienced diarrhea of varying length (mean 2.3 days, range 2 to 7 days). In contrast, no animals experienced diarrhea in the CsA or control groups. The Voclosporin group saw an average weight reduction of 3.4%, 2.0%, and 1.0% at the end of the research, respectively, which was slightly higher than that of the CsA and control groups [2].

Absorption, Distribution and Excretion
When administered on an empty stomach, the median Tmax of voclosporin is 1.5 hours, but can range from 1-4 hours. The AUC is estimated at 7693.6 ng/mL*h and the Cmax is estimated at 955.5 ng/mL.
Voclosporin is eliminated in the urine and feces, with about 88% detected in the feces and about 2% detected in the urine.
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.
The mean apparent steady-state clearance of voclosporin is 63.6 L/h. Hepatic and renal impairment significantly reduce the clearance of voclosporin.

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Metabolism / Metabolites
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.

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

Hepatotoxicity
In large randomized controlled trials of voclosporin, serum aminotransferase levels were transiently elevated in 3% of patients, but rates were similar in controls receiving conventional therapy (2%). Similar to cyclosporine, voclosporin therapy is associated with minor increases in alkaline phosphatase and bilirubin levels, although values usually remain within the normal range. In the prelicensure studies of voclosporin, there were no instances of clinically apparent liver injury attributable to therapy. Clinical experience with this agent, however, has been limited and other calcineurin inhibitors have been found to cause rare instances of hepatic injury, which are generally cholestatic, mild-to-moderate in severity and self-limited in course once treatment is stopped.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the excretion of voclosporin into breastmilk. Because voclosporin has a molecular weight of 1214 Da and is 97%, plasma protein bound, it is unlikely to enter breastmilk in large amounts. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
The protein binding of voclosporin is approximately 97%.

[1]. ISATX247: a novel calcineurin inhibitor. J Heart Lung Transplant. 2001 Feb;20(2):161.

[2]. In vivo evaluation of the novel calcineurin inhibitor ISATX247 in non-human primates. J Heart Lung Transplant. 2003 Dec;22(12):1343-52.

Voclosporin is a homodetic cyclic peptide.
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. Voclosporin, marketed as Lupkynis, is a calcineurin-inhibitor immunosuppressant for the treatment of LN. 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. 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. In July 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended voclosporin be granted marketing authorization for use in combination with [mycophenolate mofetil] for the treatment of adult patients with active lupus nephritis.
Voclosporin is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of voclosporin is as a Calcineurin Inhibitor, and P-Glycoprotein Inhibitor, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor.
Voclosporin is an orally available calcineurin inhibitor and potent immunosuppressive agent which is used in combination with mycophenolate mofetil and corticosteroids to treat acute lupus nephritis. Voclosporin may be associated with low rate of transient serum enzyme elevations during treatment but has not been linked to instances of clinically apparent acute liver injury with jaundice.

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Drug 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.
Lupkynis is indicated in combination with mycophenolate mofetil for the treatment of adult patients with active class III, IV or V (including mixed class III/V and IV/V) lupus nephritis (LN).
Treatment of Systemic Lupus Erythematosus (SLE)
Treatment of non-infectious uveitis

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

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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.

C63H111N11O12

1214.64

1213.84

515814-01-4

6918486

White to off-white solid powder

>129

4.315

5

12

16

86

2380

12

CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C=C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C

BICRTLVBTLFLRD-PTWUADNWSA-N

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

(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-((1R,2R,E)-1-hydroxy-2-methylhepta-4,6-dien-1-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone

ISATX247 LX211 LX 214 ISATX-247 LX-211 LX-214LuveniqLupkynis LX211Voclosporin ISA247 ISAtx-247 ISAtx247ISAtx 247

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~41.17 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)