Entrectinib

Mechanism :

It inhibits the tropomyosin tyrosine receptor kinases (TRKA, TRKB, TRKC), anaplastic lymphoma kinase (ALK), protooncogene tyrosine-protein kinase ROS1, Janus Kinase 2 (JAK2), Tyrosine Kinase Non receptor 2

Indication :

Neurotrophic receptor tyrosine kinase-fusion positive solid tumors for children ≥12 years and adolescents

Dosing :

Children ≥12 years and adolescents.

BSA >1.5 square meter: 600 mg PO once a day.

BSA 1.11-1.5 square meter: 500 mg PO once a day.

BSA 0.91-1.10 square meter: 400 mg PO once a day.

BSA 0.9 square meter or less: safety not established.

Dosage changes for toxicity:

BSA >1.5 square meter-first reduction: 400 mg once daily Second reduction: 200 mg daily.

BSA 1.1-1.5 square meter-first reduction: 400 mg once daily. Second reduction: 200 mg daily.

BSA 0.91-1.10 square meter- first reduction: 300mg once a day, Second reduction: 200 mg once a day .

If anaemic or neutropenic (Grade 3/Grade 4)- Discontinue entrectinib till recovery ≤Grade 2, then continue at same dose or reduced dose.

Heart failure (Grade 2/Grade 3)- Discontinue until recovery

QTc interval >500 msec- Withhold till QTc interval returns to baseline, if risk factors are resolve continue at the same dose otherwise resume at a decreased dose.

Serious arrythmias such as Torsade de pointes, Polymorphic Ventricular tachycardia- Discontinue the drug permanently.

CNS toxicity - Intolerable Grade 2 and Grade 3-Withhold until it recovers to Grade ≤1, continue at a reduced dose.

Grade 4-Discontinue permanently.

Adverse Effect :

Neurological- Fatigue, peripheral neuropathy, ataxia, dysgeusia, headache

Gastrointestinal- Constipation, nausea, diarrhoea, increased levels of Aspartate aminotransferase and alanine aminotransferase

Genitourinary- Urinary tract infections

Endocrine- Hyperuricemia, Hypernatremia

Haematology and Oncology- Anemia, neutropenia

Cardiovascular - Edema

Ophthalmic- Visual disturbances

Renal – Increased creatinine levels

Respiratory- Breathlessness and cough

Interaction :

QT prolongation – Can enhance the effect of QTc prolonging drugs such as Amisulpride, Azithromycin, Clozapine, Domperidone

CYP3A4 inhibitors- Can increase the levels of Entrectinib such as

CYP3A4 inducers- Can decrease the levels of Entrectinib such as

Lactation :

No studied data but advised to not breastfeed during treatment and discontinue breastfeeding for 7 days after last dose

Hepatic Dose :

Grade 3 hepatotoxicity- Withhold until it recovers to grade <=1-

If it resolves within 4 weeks- continue at the same dose

If resolution occurs after 4 weeks- Permanently stop the drug

If grade 3 episodes recur but resolve within 4 weeks, then continue at a reduced dose

Pregnanacy :

Animal studies and the mechanism of action suggests fetal harm on exposure