Voclosporin

Breast Feeding; Lactation; Milk, Human; Immunosuppressive Agents

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H351 (93.3%): Suspected of causing cancer [Warning Carcinogenicity]

P203, P260, P264, P270, P280, P318, P319, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 30 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

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.

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.

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.