Entrectinib

Uses

Entrectinib is indicated for the treatment of metastatic ROS1-positive non-small cell lung cancer in adults. Entrectinib is also indicated in adults and children over 12 years old for the treatment of NTRK gene fusion-positive solid tumors which have metastasized or for which surgical resection is likely to result in severe morbidity and for which has progressed on previous therapies or for which no comparable alternative therapies are available.

Entrectinib is also used to associated treatment for these conditions: Metastatic Solid Tumors, Non-Small Cell Lung Carcinoma (NSCLC), Tumors, Solid

How Entrectinib works

Entrectinib is a tyrosine kinase inhibitor which acts on several receptors. It functions as an ATP competitor to inhibit tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, as well as proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). TRK receptors produce cell proliferation via downstream signalling through the mitogen activated protein kinase, phosphoinositide 3-kinase, and phospholipase C-γ. ALK produces similar signalling with the addition of downstream JAK/STAT activation. Inhibition of these pathways suppresses cancer cell proliferation and shifts the balance in favor of apoptosis resulting in shrinking of tumor volume.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of entrectinib.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of entrectinib.
• Take with or without food. Co-administration of food does not affect pharmacokinetics.

[Major] GENERALLY AVOID: Grapefruit juice and Seville oranges may increase the plasma concentrations of entrectinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit and Seville oranges Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but pharmacokinetic data are available for the potent CYP450 3A4 inhibitor, itraconazole.

When a single 100 mg dose of entrectinib was administered with itraconazole, entrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.7- and 6-fold, respectively.

Coadministration of entrectinib with a moderate CYP450 3A4 inhibitor is predicted to increase entrectinib Cmax and AUC by 2.9- and 3-fold, respectively.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to entrectinib may increase the risk and
MANAGEMENT: Patients should avoid consumption of grapefruit, grapefruit juice, and Seville oranges during treatment with entrectinib.

Entrectinib Disease Interaction

Moderate: CHF, liver impairment, QT prolongation, renal impairment

Volume of Distribution

Entrectinib has an apparent volume of distribution of 551 L. The active metabolite, M5, has an apparent volume of distribution of 81.1 L. Entrectinib is known to cross the blood-brain barrier.

Elimination Route

Entrectinib has a Tmax of 4-5 h after administration of a single 600 mg dose. Food does not produce a significant effect on the extent of absorption.

Half Life

Entrectinib has a half-life of elimination of 20 h. The active metabolite, M5, has a half-life of 40 h.

Clearance

The apparent clearance of entrectinib is 19.6 L/h while the apparent clearance of the active metabolite M5 is 52.4 L/h.

Elimination Route

After a single radio-labeled dose of entrectinib, 83% of radioactivity was present in the feces and 3% in the urine. Of the dose in the feces, 36% was present as entrectinib and 22% as M5.

Innovators Monograph

You find simplified version here Entrectinib