Voclosporin, sold under the brand name Lupkynis, is a calcineurin inhibitor used as an immunosuppressant medication for the treatment of lupus nephritis.
It is an analog of cyclosporine that has enhanced action against calcineurin and greater metabolic stability.
Routes of administration-By mouth
Cyclosporine, a frequently prescribed calcineurin inhibitor, is the source of voclosporin.
Voclosporin and cyclophilin A combine to produce a heterodimeric complex that binds to and inhibits calcineurin, a calcium-dependent phosphatase implicated in cytokine generation and T-cell activation.
Voclosporin is a potent inhibitor of calcineurin.
The major site for voclosporin metabolism is also moved to amino acid 9, where the resultant IM9 metabolite, is nearly eight times less powerful than voclosporin, accounts for 16.7% of all drug-related exposure.
Lupus nephritis commonly leads patients to chronic kidney failure and therefore places an emphasis on early intervention for improving treatment outcomes.
The management of lupus nephritis comprises immunosuppressive therapy to lessen inflammation and maintain renal function.
Treatment recommendations include the necessity of lowering proteinuria, a crucial indicator of long-term renal success, and achieving complete renal response.
Early treatment with voclosporin is believed to lead to more positive clinical outcomes for lupus nephritis patients.
Voclosporin is used in combination with background immunosuppressive regimen for the treatment of lupus nephritis.
Clinical data support the use of voclosporin as first-line therapy in combination with mycophenolate mofetil and low-dose glucocorticosteroid.
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.
Avoid the use of live attenuated vaccines when patients are on this medication.
Co-administration of voclosporin and other moderate to strong CYP3A4 inhibitors are avoided and if needed then reduce the dose of voclosporin.
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.
The most common adverse reactions of voclosporin: (>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.
Decreases in glomerular filtration rate occurred within the first 3 months in 71% of patients, with 78% of those resolved or improved following dose modification, and of those 64% resolved or improved within 1 month.
Decreases in glomerular filtration rate resulted in permanent discontinuation of this drug in 14% of patients and resolved in 40% within 3 months after treatment discontinuation.
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.
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 are stabilized while inflammation is reduced.
Reduction of inflammation within the kidneys prevents further renal damage.
Calcineurin inhibitors in lupus nephritis have two separate impacts on calcineurin activity: immunomodulatory effects on T-cells and stabilization of the podocyte.
Inhibition of calcineurin in T cells prevents nuclear factor of activated T cells from moving to the nucleus, which reduces the transcription of genes encoding inflammatory cytokines.
This decreases lymphocyte proliferation and T-cell mediated responses.
Calcneurin inhibitors prevents the dephosphorylation of synaptopodin in the podocyte, preserving the cytoskeleton’s stabilizing function and lowers proteinuria.
Up to 1 mg/kg, voclosporin inhibits calcineurin in a dose-dependent manner with little to no lag time from the time reaching the maximum drug concentration to the time reaching maximum calcineurin inhibition.
Voclosporin is a strong inhibitor of numerous immunological processes, such as lymphocyte proliferation, T-cell cytokine generation, and T-cell surface antigen expression.
When administered on an empty stomach, the median Tmax of of the drug is 1.5 hours.
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.
Exposure is increased in individuals with severe renal impairment (creatinine clearance [CrCL] <30 mL/min) and in those with mild or moderate hepatic impairment.
3.0% died across the three published clinical trials with voclosporin in a total with lupus nephritis.
There is a significant association was found between voclosporin blood levels and estimated calcineurin inhibition.
Voclosporin is the first oral treatment for lupus nephritis to receive approval in the USA.