Entrectinib: Uses, Interactions, Mechanism Of Action

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Understanding Entrectinib: Uses, Mechanism of Action, and Drug Interactions
The development of targeted cancer therapies has revolutionized the approach to oncology. Among these innovative agents, entrectinib stands out as a selective inhibitor designed to target specific genetic alterations that drive cancer progression. With its ability to address multiple tumor types driven by particular gene fusions, entrectinib represents a shift toward personalized medicine in oncology.

In this blog, we will explore the key clinical uses of entrectinib, its mechanism of action, and potential drug interactions clinicians and patients should be aware of.
What Is Entrectinib?
Entrectinib is an oral small-molecule tyrosine kinase inhibitor (TKI) developed to target specific gene rearrangements that are known to promote cancer growth. It belongs to a class of medications that selectively inhibit the activity of certain proteins involved in cell signaling pathways that regulate cell proliferation and survival.
Entrectinib is notable for its ability to cross the blood-brain barrier, making it effective for cancers ...
... that have metastasized to the central nervous system (CNS), a common and difficult-to-treat site of disease in many malignancies.
Clinical Uses of Entrectinib
Entrectinib is primarily used to treat patients whose tumors harbor specific genetic alterations, namely:
NTRK Gene Fusion-Positive Solid Tumors
Entrectinib is indicated for the treatment of solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, regardless of tumor type. These fusions lead to the production of abnormal TRK fusion proteins, which drive uncontrolled cellular growth. Entrectinib is used in cases where:

There are no satisfactory alternative treatments available.

The cancer has metastasized or is inoperable.

ROS1-Positive Non-Small Cell Lung Cancer (NSCLC)
In NSCLC, gene rearrangements involving ROS1 are found in a small subset of patients. These gene fusions activate oncogenic signaling pathways, making entrectinib a rational choice as a ROS1 inhibitor.

The use of entrectinib in these contexts exemplifies the growing trend of tissue-agnostic cancer therapies, which are guided more by genetic markers than by the cancer’s site of origin.
Mechanism of Action
Entrectinib acts by selectively inhibiting the tyrosine kinases encoded by the following genes:
NTRK1, NTRK2, and NTRK3: These genes encode for TRKA, TRKB, and TRKC proteins, respectively. When abnormally fused with other genes, these proteins can trigger constitutive activation of downstream signaling pathways like MAPK, PI3K-AKT, and PLCγ, leading to unchecked cell division.

ROS1: A receptor tyrosine kinase implicated in oncogenic fusion events in lung cancer.

ALK (Anaplastic Lymphoma Kinase): Entrectinib also has activity against ALK, though this is not its primary approved indication.

By blocking the ATP-binding site of these kinases, entrectinib halts downstream signaling that drives proliferation and survival of tumor cells. The compound's ability to penetrate the CNS further allows it to combat brain metastases, a significant advantage over some earlier TKIs.
Pharmacokinetics and Administration
Entrectinib is administered orally and is generally taken once daily. It undergoes metabolism primarily in the liver, predominantly via the CYP3A4 enzyme, a feature that has important implications for potential drug interactions.
The half-life of entrectinib is approximately 20 hours, supporting its once-daily dosing. Peak plasma concentrations are typically reached within 4 to 6 hours after administration.
Potential Drug Interactions
Given its metabolism via CYP3A4, entrectinib is susceptible to several significant drug interactions. These include:
1. CYP3A4 Inhibitors
Drugs that inhibit CYP3A4 can increase plasma levels of entrectinib, potentially raising the risk of toxicity. Examples include:
Ketoconazole

Itraconazole

Clarithromycin

Grapefruit juice (a dietary source)

2. CYP3A4 Inducers
Conversely, drugs that induce CYP3A4 can decrease entrectinib levels, reducing its efficacy. Examples include:
Rifampin

Carbamazepine

Phenytoin

St. John’s Wort (a common herbal supplement)

Co-administration with strong inducers is generally discouraged.
3. QT Interval-Prolonging Drugs
Entrectinib may modestly prolong the QT interval, a measurement of cardiac electrical activity. Concomitant use with other QT-prolonging drugs (e.g., certain antiarrhythmics, antipsychotics, or antibiotics) may increase the risk of arrhythmias.
4. P-glycoprotein (P-gp) Substrates
Entrectinib may inhibit P-glycoprotein, potentially increasing exposure to drugs that are P-gp substrates, such as digoxin.
Side Effects and Monitoring
Common side effects of entrectinib include:
Fatigue

Dizziness

Nausea and vomiting

Constipation

Weight gain

Anemia

More serious adverse effects can include cardiomyopathy, QT prolongation, central nervous system effects (e.g., cognitive disturbances), and skeletal fractures, particularly in pediatric populations. Regular monitoring of cardiac function, liver enzymes, and neurologic status is advised during therapy.
Conclusion
Entrectinib is a potent, targeted therapy designed for cancers driven by specific gene fusions, notably involving NTRK and ROS1. Its effectiveness across tumor types, ability to cross the blood-brain barrier, and relatively well-tolerated safety profile make it a valuable tool in modern oncology.
However, like all targeted therapies, its use must be guided by appropriate molecular diagnostics, and potential drug interactions must be carefully managed.
URL: For more information, visit Vasista Pharma: Entrectinib: Uses, Interactions, Mechanism of Action