Voclosporin

Uses

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

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.

Voclosporin is also used to associated treatment for these conditions: Nephritis, Lupus

How Voclosporin works

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.

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.

Food Interaction

• 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.

[Major] GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of voclosporin.

The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

Because voclosporin prolongs the QT interval in a dose-dependent manner, high plasma levels of voclosporin may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes.

In drug interaction studies, coadministration with multiple doses of moderate CYP450 3A4 inhibitors fluconazole or diltiazem is predicted to increase the peak plasma concentration (Cmax) and the area under the 12-hour plasma concentration-time curve (AUC 0-12) of voclosporin by approximately 2- and 3-fold respectively.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

In addition, moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using voclosporin, which has been reported with the use of voclosporin.

Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

ADJUST DOSING INTERVAL: Consumption of food can decrease the rate and extent of gastrointestinal absorption of voclosporin.

When administered with either low- or high-fat meals, the peak plasma concentration (Cmax) of voclosporin decreased by 29% to 53% and systemic exposure (AUC) decreased by 15% to 25%.

MANAGEMENT: Patients receiving voclosporin therapy should be advised to avoid consumption of grapefruit or grapefruit juice.

Voclosporin therapy should be administered at least 1 hour before or 2 hours after meals.

Patients should also receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their doctor.

If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended.

Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

Voclosporin Hypertension interaction

[Moderate] The use of voclosporin causes hypertension.

Exercise care when using this agent in hypertensive patients, including patients on antihypertensive drugs.

It is recommended to monitor blood pressure regularly during treatment and treat new-onset hypertension and exacerbations of preexisting hypertension according to medical practices.

If a patient experiences increases in blood pressure that cannot be managed with dose reduction or other appropriate medical intervention, consider treatment discontinuation.

Voclosporin Disease Interaction

Major: infections, liver dysfunctionModerate: nephrotoxicity, neurotoxicities, PRCA, QT prolongation, vaccination, Voclosporin – hypertension

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.

Elimination Route

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.

Half Life

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

Clearance

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

Elimination Route

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

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