Entrectinib

560.6

560.64

L5ORF0AN1I

C114984

L01EX14|L - Antineoplastic and immunomodulating agents

85.5

5.7

1.340±0.06 g/cm3(Predicted)

717.5±60.0 °C(Predicted)

387.7±32.9 °C

1.672

In the prelicensure clinical trials of entrectinib in patients with NTRK fusion gene positive solid tumors and ROS1 fusion gene positive non-small cell lung cancer, liver test abnormalities were frequent although usually mild. Some degree of ALT elevation arose in 38% of entrectinib treated patients, but were above 5 times the upper limit of normal (ULN) in only 2% to 3% (although the incidence may have been underestimated as 4.5% of patients had no post-treatment liver function tests). In these trials that enrolled approximately 355 patients, entrectinib was discontinued early due to increased AST or ALT in 0.8% of patients. Thus, in preregistration trials of entrectinib there were no instances of clinically apparent liver injury with jaundice, but therapy was associated with a high rate of serum ALT elevations and the total clinical experience with its use has been limited. The product label for entrectinib recommends monitoring for routine liver tests before, at 2 week intervals during the first month of therapy, and monthly thereafter as clinically indicated.

Entrectinib is over 99% bound to plasma proteins.

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.|FDA Label|Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients 12 years of age and older with solid tumours expressing a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, andwho have not received a prior NTRK inhibitorwho have no satisfactory treatment options.Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1 positive, advanced non small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.|Treatment of all conditions induded in the category of malignant neoplasms ( except haematopoietic and lymphoid tissue neoplasms)|Drug: Entrectinib

Entrectinib is an oral selective inhibitor of the neurotrophic T receptor kinase (NTRK) and ROS1 that is used to treat solid tumors with NTRK gene fusion and non-small cell lung cancer with ROS1 mutations. Serum aminotransferase elevations are common during therapy but clinically apparent liver injury is rare, although it has been reported.

Antineoplastic Agents, Kinase Inhibitors

Entrectinib and its active metabolite suppress several pathways which contribute to cell survival and proliferation. This suppression shifts the balance in favor of apoptosis thereby preventing cancer cell growth and shrinking tumors.

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

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

CYP3A4 is responsible for 76% of entrectinib metabolism in humans including metabolism to the active metabolite, M5. M5 has similar pharmacological activity to entrectinib and exists at approximately 40% of the steady state concentration of the parent drug. In rats, six in vivo metabolites have been identified including N-dealkylated, N-oxide, hydroxylated, and glucuronide conjugated metabolites.

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

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.

entrectinib

Human drugs -> Rozlytrek -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients