Vimseltinib

MECHANISM OF ACTION

Vimseltinib is a selective, oral inhibitor of colony-stimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase that plays a central role in regulating the survival, proliferation, and differentiation of macrophages and other myeloid cells. In conditions like tenosynovial giant cell tumor (TGCT), overproduction of CSF1 (the ligand for CSF1R) leads to the recruitment and accumulation of macrophages and other immune cells that drive tumor growth, inflammation, and joint destruction.

Vimseltinib works by:

Blocking CSF1R activity, preventing its activation by CSF1 and IL-34 (its ligands). Inhibiting the downstream signaling pathways (such as PI3K/AKT and MAPK) involved in macrophage survival and proliferation. Reducing the number of tumor-associated macrophages, which are key contributors to the immunosuppressive tumor microenvironment in TGCT. Suppressing tumor growth and inflammation by limiting the expansion of pathologic myeloid cells and remodeling the tumor microenvironment. This targeted mechanism allows vimseltinib to address the underlying biology of TGCT, particularly in patients who are not candidates for surgery due to the tumor’s location or recurrence risk.

PHARMACOKINETICS

Absorption

Vimseltinib is absorbed rapidly after oral administration, reaching its peak concentration in about one hour. Its absorption is not significantly affected by food, and it has a long elimination half-life of approximately 6 days. 

Distribution

The volume of distribution for vimseltinib is 90 L, which is substantially larger than the total body water in an average adult. In human plasma, vimseltinib is 96.5% bound to proteins. The elimination half-life of vimseltinib is approximately 6 days.

Metabolism

Vimseltinib is primarily metabolized through oxidation, N-demethylation, and N-dealkylation, with further oxidation and dehydrogenation as secondary pathways. Despite being metabolized in the liver, cytochrome P450 (CYP450) enzymes are not considered a major part of its metabolism, and vimseltinib does not significantly inhibit or induce CYP450 isoforms. 

Excretion

Vimseltinib is primarily eliminated from the body via excretion in the feces and urine after being metabolized. Approximately 81% of a dose is recovered through these two routes.

PHARMACODYNAMICS

Vimseltinib’s pharmacodynamics center on its inhibition of the CSF1 receptor (CSF1R), which is expressed on monocytes, macrophages, and osteoclasts. By blocking the binding of the ligands CSF-1 and IL-34, vimseltinib disrupts CSF1R-mediated signaling pathways. This leads to a reduction in inflammatory mediator production, suppression of tumor-associated macrophage (TAM) growth and their immunosuppressive activity, and promotes increased T-cell infiltration and anti-tumor immune responses within the tumor microenvironment. Collectively, these actions contribute to reduced tumor cell proliferation, decreased inflammation, and improved physical function.

DOSAGE AND STRENGTHS

Recommended starting dose: 30 mg orally, twice weekly, with at least 72 hours between doses. 

It Can be taken with or without food. 

Capsules must be swallowed whole, do not open, break, or chew them.

Available capsule strengths are:

• 14 mg 

• 20 mg 

• 30 mg

DRUG INTERACTIONS

Vimseltinib can cause drug interactions by inhibiting transport proteins like P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), and Organic Cation Transporter 2 (OCT2), which can increase the concentration of other drugs in the body and potentially lead to adverse effects. Common medications that may have interactions include blood thinners like dabigatran, heart medications like dofetilide and digoxin, and cholesterol-lowering drugs like atorvastatin and simvastatin. Because of this risk, it is best to avoid concomitant use with certain drugs, and patients taking blood thinners should administer vimseltinib at least four hours before the other medication. Additionally, patients should avoid consuming grapefruit and limit alcohol due to the potential for adverse effects, particularly on the liver.

FOOD INTERACTIONS

Vimseltinib can be taken with or without food, as meals do not significantly affect its absorption. You should, however, avoid grapefruit and grapefruit juice because they can interfere with how the medication is processed. It is also best to limit or avoid alcohol, as both vimseltinib and alcohol can increase the risk of liver damage.

CONTRAINDICATIONS

As of its approval in February 2025 under the brand name Romvimza, there are no specific contraindications listed for vimseltinib in its U.S. Prescribing Information. However, the prescribing information includes important warnings and precautions for certain conditions. 

SIDE EFFECTS

• Common side effects:

• Periorbital edema.

• Fatigue.

• Rash.

• Edema.

• Increased liver enzymes.

• Increased cholesterol levels.

• Decreased white blood cell counts.

Serious side effects and warnings:

• Liver problems.

• Allergic reactions.

• Birth defects.

• Infertility.

OVERDOSE

Potential symptoms of an overdose:

• Intensified liver problems.

• Severe allergic reaction.

• Exaggerated swelling.

• Worsened fatigue and weakness.

• Abnormal results for Lab tests.

• Neuropathy.

TOXICITY

Vimseltinib is generally well tolerated but can cause several toxicities, most notably elevated liver enzymes (hepatotoxicity), edema, fatigue, rash, and blood count changes such as neutropenia. Other reported effects include increased cholesterol, hypertension, and elevated serum creatinine, which may not reflect true kidney dysfunction. Liver function should be closely monitored, especially in patients with pre-existing hepatic conditions. The drug may cause fetal harm, so it is contraindicated in pregnancy, and contraception is advised during treatment. Rare allergic reactions may occur due to color additives like tartrazine. Most side effects are mild to moderate and manageable with dose adjustments.