Summary of Clinical Use

Used in the treatment of unresectable or metastatic melanoma in patients with the BRAF-V600 mutation. In November 2017, the FDA expanded approval to include treatment of Erdheim-Chester disease with BRAF-V600 mutation [1].

Mechanism Of Action and Pharmacodynamic Effects

Vemurafenib is a low molecular weight, orally available, inhibitor of BRAF serine-threonine kinase. Activating mutations in the BRAF gene at valine 600 (V600) can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. In biochemical assays vemurafenib can potently inhibit BRAF kinases with a number of these activating V600 mutations. Vemurafenib is notably potent at the BRAF V600E substitution (VAR_018629), a mutation known to activate the mitogen-activated kinase (MAPK) pathway resulting in cell growth, proliferation, and metastasis. Vemurafenib blocks these downstream processes to inhibit tumour growth and eventually trigger apoptosis. Vemurafenib is not known to have antitumour effects in melanoma cell lines expressing wild-type BRAF.

Pharmacokinetics

Absorption/Distribution

After oral administration of vemurafenib, it is well absorbed. In patients peak concentrations are reached in 3 hours although there is high variability in exposure between patients. Bioavailability is unknown. Albumin and α-1 acid glycoprotein protein binding is more than 99%. Parent drug constitutes 95% of the components in plasma with its metabolites representing only 5%.

Biotransformation/Metabolism

Vemurafenib is metabolized predominantly by CYP3A4. The parent drug constitutes 95% of the components in plasma with its metabolites representing only 5%.

Elimination

Verumafenib is excreted via feces (94%) and urine (1%).

Population pharmacokinetics

The pharmacokinetics of vemurafenib are not significantly affected by age or gender and there is insufficient data to evaluate potential differences in the pharmacokinetics of vemurafenib by race. The pharmacokinetics have not been evaluated in children.

Organ function impairment

Apparent Cl was similar in patients with mild and moderate renal impairment compared with patients with healthy renal function. Pharmacokinetic data are only available for 1 patient with severe renal impairment; the need for dosage adjustment in this patient population cannot be determined. Apparent Cl was similar in patients with mild and moderate hepatic impairment compared with patients with healthy hepatic function. Pharmacokinetic data are only available for 3 patients with severe hepatic impairment; the need for dosage adjustment in this patient population cannot be determined.

External links

For extended ADME data see the following: Electronic Medicines Compendium (eMC) Drugs.com European Medicines Agency (EMA)