Voclosporin

Absorption

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.

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.

Description

Voclosporin, a structurally similar analogue of cyclosporin A, is a new type of calcineurin inhibitor. It has been modified to increase its activity by 3-4 times and exhibits a dual and synergistic mechanism. This drug works by blocking the expression of IL-2 and T cell-mediated immune response, stabilizing renal podocytes. Compared to cyclosporin, voclosporin has the advantage of having less impact on cholesterol and triglycerides and a lower risk of diabetes. In February 2021, vorcyclosporine was approved by the FDA for use in combination immunosuppressive regimens in adult patients with active, lupus nephritis.

The Uses of Voclosporin

Voclosporin is a new agent for the treatment of noninfectious uveitis. Uveitis is an inflammatory, putative Th1-mediated autoimmune disease that affects various parts of the eye and is a leading cause of visual loss . Voclosporin, a rationally designed novel calcineurin inhibitor, exhibits a favorable safety profile, a strong correlation between pharmacokinetic and pharmacodynamic response, and a wide therapeutic window.

The Uses of Voclosporin

A new agent for the treatment of noninfectious uveitis. Uveitis is an inflammatory, putative Th1-mediated autoimmune disease that affects various parts of the eye and is a leading cause of visual loss. Voclosporin, a rationally designed novel calcineurin inhibitor, exhibits a favorable safety profile, a strong correlation between pharmacokinetic and pharmacodynamic response, and a wide therapeutic window. Immunosuppressant.

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.
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.

Indications

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.

Definition

ChEBI: Voclosporin is a homodetic cyclic peptide. It is a semi-synthetic calcineurin (CN) inhibitor that exhibits potent immunosuppressive activity.

Pharmacokinetics

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.

Clinical Use

Voclosporin (Lupkynis(TM)) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis.

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.

References

1. Voclosporin: First Approval DOI: 10.1007/s40265-021-01488-z
2. Voclosporin: A Novel Calcineurin Inhibitor for the Treatment of Lupus Nephritis DOI: 10.1177/10600280221075331