Voclosporin

Mechanism of Action

Voclosporin is an oral CNI that binds cyclophilin A in T-cells.[2] The drug molecule has a cyclic undecapeptide structure of 11 amino acids, originally isolated from a fungus species named Beauveria nivea.[5][6] There is an additional single carbon extension to the amino acid-1 position.[2] This structural change results in a molecule with higher binding potency to cyclophilin A and increased inhibition of calcineurin.[2][7] The voclosporin-cyclophilin binding competitively inhibits calcineurin from dephosphorylating the nuclear factor of activated T-cells (NFAT-P) to the nuclear factor of activated T-cells (NFAT).[2] 

Inhibition of this critical metabolic step precludes NFAT from activating the translation and transcription of various cytokines produced by T-helper-1 cells, including interleukin-2 (IL-2). IL-2 is a T-cell growth factor vital for the proliferation of T cells and for the generation of effector and memory cells.[2][8][9] The inhibited production of IL-2 prevents the proliferation and differentiation of cytotoxic and other effector T cells.[7][9]

Activated calcineurin dephosphorylates synaptopodin which is then metabolized by a lysosomal protease.[10] This breakdown ultimately results in the destabilization of the podocyte cytoskeleton and increases proteinuria.[7][10] Voclosporin, by inhibiting this dephosphorylation pathway, promotes actin cytoskeleton stabilization of the podocytes and thus reduces proteinuria.[8] Voclosporin inhibits the dephosphorylation pathway by binding the phosphorylated synaptopodin with the 14-3-3 protein.[2][7][10] 

The modification of amino acid-1 changes the primary site of metabolism to the amino acid-9 position. The modification results in a lower degree of competitive inhibition and a low metabolite load.[5][11] This favorable metabolic profile also improves serum drug levels in a dose-proportional manner over a wide therapeutic range. This particular property means that therapeutic drug monitoring is not required for voclosporin.[5] 

Pharmacokinetics

The major circulating component is voclosporin. A major metabolite of voclosporin with approximately 8-fold less potency than the parent molecule represented about 16.7% of total exposure in whole human blood.[3] Around 99% of the drug is metabolized via cytochrome P450 3A4 (CYP3A4) isoform and excreted in feces, as confirmed after administration of radiolabeled voclosporin.[2][3]

After six days of twice daily dosing, voclosporin can achieve steady-state concentrations.[3] The maximum concentration (Cmax) of voclosporin can be reached within 1 to 4 hours if taken on an empty stomach.[3] The pharmacokinetics of voclosporin is not influenced by age, gender, body weight, race, total bilirubin, and serum albumin in a clinically relevant manner.[3] There was no significant lag between the interval taken to reach maximum voclosporin concentrations and the time taken for maximum inhibition of calcineurin.[3][12] 

When administered with low- or high-fat meals in healthy adults, Cmax decreases by 29% to 53%.[3] Voclosporin distributes extensively in red blood cells. The distribution between whole blood and plasma is dependent on concentration and temperature.[3] Given voclosporin’s high protein binding of 97%, its apparent volume of distribution of 2154 Liters. Voclosporin’s mean apparent clearance is 63.6 L/h at steady-state with a mean terminal half-life of around 30 hours.[3]

Administration

Voclosporin is dosed and administered in the following manner:

In adults with active lupus nephritis, when combined with background immunosuppressive therapy:

• 23.7 mg twice daily by mouth. To ensure adequate absorption, voclosporin must be taken on an empty stomach.[13]

Dose adjustments may be necessary for patients with renal dysfunction and are as follows:

• If eGFR is <60 mL/min/1.73 m² and reduced from baseline by >20% and <30%, the dose should be reduced by 7.9 mg twice daily.[2]
• Upon re-assessing the eGFR within 2 weeks, if it is still reduced from baseline by >20%, reduce the dose again by 7.9 mg twice daily.[3]
• If eGFR is <60 mL/min/1.73 m² and reduced from baseline by >30%, voclosporin should be discontinued.[2][3]
• For patients with a decrease in dose due to eGFR, consider increasing the dose by 7.9 mg twice daily for each eGFR measurement that is ≥80% of baseline; do not exceed the starting dose.
• If voclosporin is used in patients with severe renal impairment at baseline (creatinine clearance <30 mL/min the recommended starting dose is 15.8 mg twice a day.[2][3]
• In patients with end-stage renal disease (ESRD) with or without hemodialysis, the pharmacokinetics of voclosporin is unknown.[2][3]

Dose adjustments may be necessary for patients with hepatic dysfunction and are as follows:

• In patients with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B), the recommended dose is 15.8 mg twice daily.
• Voclosporin is not recommended in patients with severe hepatic impairment (Child-Pugh C).

Drug Interactions

• Voclosporin is a CYP3A4 substrate. When co-administered with other medications that are moderate or potent CYP3A4 inhibitors, it reduces clearance and increases voclosporin levels. The increased levels can increase the risk of voclosporin-associated adverse reactions.[3]
• AReducingthe dose of voclosporin is recommended when co-administered with moderate CYP3A4 inhibitors such as verapamil, fluconazole, and diltiazem.[7]
• When voclosporin is co-administered with moderate or strong CYP3A4 inducers, the combination increases voclosporin metabolism, reducing the efficacy of voclosporin.[3][7]
• Voclosporin is an inhibitor of P-glycoprotein (P-gp). Hence, caution is required upon co-administration with other P-gp inhibitors such as verapamil, sertraline, erythromycin, and reserpine. If P-gp substrates with a narrow therapeutic index, such as digoxin, are co-administered with voclosporin, then a dose reduction of P-gb substrates may be required.[2][14]
• There is no clinically significant interaction between voclosporin and mycophenolate mofetil. There is no necessity for dose adjustment when these medications are administered simultaneously.[4]

Adverse Effects

Voclosporin, similar to other CNIs, can cause acute and chronic nephrotoxicity. The major adverse effect of voclosporin is reduced glomerular filtration rate. Nephrotoxicity is usually dose-dependent and can be influenced by drug–drug interactions and intracellular concentrations. Acute nephrotoxicity can be caused by a reversible glomerular filtration rate (GFR) decrease. Chronic nephrotoxicity can be marked by nonspecific arteriolar lesions, focal and segmental and global glomerular sclerosis, patchy interstitial fibrosis, and tubular atrophy, which can progress to irreversible lesions.[7]

Hypertension is a common adverse effect of voclosporin; it can be explained by the vasoconstrictive effect of voclosporin on afferent pre-glomerular arterioles. Hypertension also contributes to decreased eGFR and subsequent salt and water retention. Arterial hypertension is less severe with voclosporin when compared to other CNIs.[2][7][11]

Voclosporin can cause neurotoxicity, including posterior reversible encephalopathy syndrome (PRES), delirium, seizure, coma, tremors, paresthesia, headache, and mental status changes.[7]

Although clinically apparent acute liver injury with jaundice has not been classically linked to voclosporin, it can be associated with a low rate of transient serum enzyme elevations during treatment.[6]

Electrolyte disturbances of hyperkalemia and hypomagnesemia can occur with the administration of calcineurin inhibitors, including voclosporin. Hypomagnesemia can be caused by reduced renal reabsorption of magnesium and chronic renal magnesium wasting. Due to the inhibition of calcineurin, there is reduced expression of Na-K-2Cl-cotransporter on the tubular epithelial cells, which plays a role in hyperkalemia. These electrolyte abnormalities may be responsible for voclosporin prolonging QTc interval. Dose-dependent QTc prolongation was noted after a single dose of voclosporin 0.5 to 4.5 mg/kg (which is up to 9-fold higher than the therapeutic dose).[2][12][13]

The exact association between pure red cell aplasia (PRCA) and voclosporin is unknown. If a patient develops PRCA while on treatment with voclosporin, the discontinuation of voclosporin should be considered. Voclosporin may increase the risk of developing lymphomas and malignancies predominantly of the skin.[4][7]

Other adverse effects reported with voclosporin are as follows, and these can be approached on a case-by-case basis, weighing the benefits and the risks.

• Diarrhea
• Nausea with vomiting
• Headache
• Anemia
• Cough
• Increased risk of infections such as upper respiratory tract infections
• Peripheral edema
• Alopecia
• Insomnia

Contraindications

• The co-administration of voclosporin with potent CYP3A4 inhibitors, for example, ketoconazole, itraconazole, and clarithromycin, are contraindicated.[15]
• In patients with eGFR <45 mL/min/1.73 m², using voclosporin is contraindicated unless benefits exceed risks.[3][15]
• Voclosporin is not recommended in patients with hypertension with a baseline blood pressure of >165/105 mm Hg.[3][7]
• Although there is not much data about the use of voclosporin in pregnant women and lactating women, voclosporin formulation contains alcohol, and the current recommendation is that voclosporin should be avoided in pregnant and lactating patients.[16]

Monitoring

The patient's blood pressure should also be recorded before treatment initiation and monitored biweekly for the first month of treatment. After which, it should be monitored as indicated clinically.[5][7]

An accurate baseline estimated glomerular filtration rate (eGFR) should be established before initiating voclosporin, and eGFR should be assessed every 2 weeks for the first month of treatment and every 4 weeks after that.[13]

Voclosporin and mycophenolate mofetil (MMF) can be administered concomitantly without adjusting the dose of MMF. There is no risk of the emergence of MMF-related adverse effects following the discontinuation of voclosporin.[4]

Toxicity

In the event of overdose or toxicity, there are currently no reversal agents approved for voclosporin by the FDA. The FDA-boxed warnings include an increased risk of developing serious infections and malignancies.

Enhancing Healthcare Team Outcomes

The management of autoimmune diseases, such as SLE/LN, is a complex process that imposes a significant cost burden on both patients and the healthcare system. Voclosporin, a novel immunosuppressive agent, is used in combination with background immunosuppressive therapy for patients with lupus nephritis. The utilization of background immunosuppressive therapies in conjunction with voclosporin is a critical aspect of LN management.

To ensure the best possible outcomes for patients, an interprofessional healthcare team comprising various specialties is essential. Despite the improved pharmacodynamics of voclosporin compared to previous calcineurin inhibitors (CNIs), it can still lead to severe adverse effects. Therefore, regular patient visits and frequent monitoring of vital signs and laboratory tests are crucial to prevent potential complications. Primary care providers, including advanced practice practitioners, should be well-informed about significant adverse effects and maintain open communication with rheumatologists and nephrologists to address any concerns that may arise.

Given the potential for drug interactions, collaborative patient care involving pharmacists is paramount. Accurate and comprehensive medication reconciliation, along with verification of the appropriate dose adjusted for creatinine clearance, should be conducted by pharmacists. If any discrepancies are noted, they should promptly communicate them to other members of the healthcare team.

Close monitoring for adverse effects is necessary for all patients receiving voclosporin, and nurses often play a key role in being the first to receive reports of adverse events from patients. This information can then be shared with other members of the healthcare team for collaborative decision-making regarding further steps. Social workers have a crucial role in identifying barriers to care, including financial constraints that may hinder medication affordability. The social work team can provide the necessary resources and support to assist patients in overcoming these challenges.

In summary, the use of voclosporin in the treatment of lupus nephritis requires an interprofessional healthcare team consisting of physicians, physician extenders, nurses, pharmacists, and social workers. Although team members come from various disciplines, effective collaboration and communication are essential to achieve optimal outcomes for patients.[Level 5]