Entrectinib

Mechanism of effect

Entrectinib inhibits tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC. TRKA, TRKB, and TRKC are encoded by neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Entrectinib also inhibits proto-oncogenic tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). M5 (the major active entrectinib metabolite) demonstrated similar activity (in vitro) against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains act as oncogenic drivers to promote hyperactivation of downstream signaling pathways, resulting in unchecked cell proliferation.

Pharmacodynamic

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.

Pharmacokinetics

Steady-state achieved within 1 week for entrectinib and 2 weeks for M5

Peak plasma time: 4-6 hr (entrectinib plasma level; 600-mg dose)

Peak plasma concentration

Single dose: 2250 nM (entrectinib); 622 nM (M5)
Steady-state: 3130 nM (entrectinib); 1,250 nM (M5

AUC

Single dose: 31,800 nM·hr (entrectinib); 10,200 nM·hr (M5)
Steady-state: 48,000 nM·hr (entrectinib); 24,000 nM·hr (M5)

Protein bound: >99% (entrectinib and M5)

Vd: 551 L (entrectinib); 81.1 L (M5)

Metabolism

Metabolized primarily by CYP3A4 (~76%); forms active metabolite M5 (formed by CYP3A4); the only major active circulating metabolite identified

Clearance: 19.6 L/hr (entrectinib); 52.4 L/hr (M5)

Half-life: 20 hr (entrectinib); 40 hr (M5)

Excretion: Feces (83% [36% as unchanged entrectinib; 22% as M5]) urine (3%)

Drug indications

non–small cell lung cancer

-Non-small Cell Lung Cancer

-Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors

Dosage

-Non-small cell lung cancer (metastatic), ROS1-positive: Oral: 600 mg once daily until disease progression or unacceptable toxicity.

-Solid tumors (with neurotrophic receptor tyrosine kinase gene fusion): Oral: 600 mg once daily until disease progression or unacceptable toxicity.

PEDIATRIC

-Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors

<12 years: Safety and efficacy not established

≥12 years

Recommended dosage is based on body surface area (BSA)

0.91-1.1 m²: 400 mg PO qDay
1.11-1.5 m²: 500 mg PO qDay
>1.5 m²: 600 mg PO qDay

Continue until disease progression or unacceptable toxicity

Drug contraindications

None

Side effects

Diarrhea , Headache , edema , nausea , abdominal pain , vertigo , hypotension , Urinary tract infection , pulmonary embolism , Hypocalcemia , Creatinine increased , peripheral nephropathy , pneumonia , Hypophosphatemia , Weight increase , difficulty urinating , tiredness , Rash , Back pain , Syncope , acute respiratory failure

Increased creatinine -Anemia -Hyperuricemia -Fatigue -Constipation -Dysgeusia -Increased AST -Edema -Lymphopenia -Increased ALT -Hyponatremia -Diarrhea -Dysesthesia -Nausea -Hypocalcemia -Hypophosphatemia -Dyspnea -Increased lipase -Hypoalbuminemia -Dizziness -Neutropenia -Myalgia -Cognitive impairment -Increased amylase -Hyperkalemia -Increased weight -Increased alkaline phosphatase -Cough -Vomiting -Pyrexia -Arthralgia -Vision disorders -Peripheral sensory neuropathy -Headache -Hypotension -Ataxia -Abdominal pain -Sleep -Urinary tract infection -Decreased appetite -Muscular weakness -Back pain -Extremity pain -Rash -Mood disorders -Dehydration -Lung infection - Pneumonia -Pleural effusion -Sepsis -Pulmonary embolism -Respiratory failure -Hyperglycemia -Hypoxia - Syncope -Muscular weakness -Ataxia - Sleep disorders -Decreased appetite

Interactions

Carbamazepine , Dolasetron , Quinine , sparfloxacin , Paliperidone , Pazopanib , Pimavanserin , lenvatinib , Amiodarone , Aprepitant , Erythromycin , Ofloxacin , Olanzapine , Itraconazole , indacaterol , lumefantrine , tucatinib , Netupitant , cenobamate , tazemetostat , Eslicarbazepine acetate , telotristat , voxelotor , stiripentol , Pasireotide , ozanimod , lefamulin , lofexidine , osilodrostat , selpercatinib , glasdegib , Ceritinib , Eliglustat , Romidepsin , conivaptan , quinupristin and dalfopristin , Pitolisant , Istradefylline , Larotrectinib , Siponimod , Rucaparib , elagolix , Fedratinib , Triclabendazole , Crizotinib , Telavancin , Deutetrabenazine , Asenapine , Artemether , ezogabine , Iloperidone , Degarelix , encorafenib , Efavirenz , Bexarotene , Tipranavir , cobicistat , Fostamatinib , Letermovir , Goserelin , Anagrelide , Idelalisib , Ivacaftor , brigatinib , Arsenic trioxide , Ribociclib , Dofetilide , Ibutilide , Eribulin , Inotuzumab‎ , Armodafinil , vemurafenib , Osimertinib , Chloroquine , Indinavir , Procainamide , Panobinostat , primaquine , Fosamprenavir , Mifepristone , vandetanib , Lopinavir , Droperidol , Histrelin , Nefazodone , dronedarone , ritonavir , saquinavir , nelfinavir , Pentamidine , Quetiapine , Toremifene , Quinidine , Grapefruit , Ziprasidone , Leuprolide acetate , escitalopram , Clofazimine , Atazanavir , Ranolazine , Darunavir , Clobazam , Clotrimazole , Clozapine , Flecainide , Bicalutamide , formoterol , Verapamil , Voriconazole , Ketoconazole , Clarithromycin , Chloramphenicol , Chlorpromazine , Methadone , Modafinil , Moxifloxacin , Nilotinib , Haloperidol , Hydroxychloroquine , Fluoxetine , Fluconazole , Fingolimod , Granisetron , Lapatinib , Levofloxacin , Sotalol , Sorafenib , Ciprofloxacin , Citalopram , Cyclosporine , Fluvoxamine , Desipramine , Disopyramide , Diltiazem , Risperidone , Sunitinib , Sertraline , Tetracycline , Trazodone , Triptorelin , Thioridazine , Gemifloxacin , Doxycycline , Isoniazid , Imatinib , Propafenone , Posaconazole , Pimozide , Tetrabenazine , Lopinavir and Ritonavir , oleandomycin , Bepridil , bedaquiline , Gemtuzumab , vemurafenib , Halaven

abametapir-erythromycin ethylsuccinate-erythromycin lactobionate-erythromycin stearate-netupitant/palonosetron-schisandra-

Alerts

-Increase of fractures reported; promptly evaluate patients with signs or symptoms (eg, pain, changes in mobility, deformity) of fractures

-Increased liver transaminase reported;

-Hyperuricemia reported, as well as elevated uric acid levels;

-Vision disorders have occurred, including blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, and vitreous floaters

-Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, fetal harm may occur when administered to a pregnant woman

- QT prolongation reported; patients with at least 1 post-baseline ECG assessment experienced prolonged QT interval of >60 ms after starting treatment

- CNS adverse reactions reported, including cognitive impairment, mood disorders, dizziness, and sleep disturbances

- CHF occurred in clinical trials.Among patients with CHF, median time to onset was 2 months.Myocarditis in the absence of CHF was also documented

Points of recommendation

- monitor liver tests every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated

- assess serum uric acid levels prior to initiation and periodically during treatment

- Assess QT interval and electrolytes at baseline and periodically during treatment

- Instruct patients not to drive or operate hazardous machinery if experiencing CNS adverse reactions

- Assess left ventricular ejection fraction before initiation in patients with symptoms or known risk factors for CHF

- Grapefruit products are CYP3A4 inhibitors; avoid these products during treatment

- Avoid coadministration with other products with a known potential to prolong QT interval

- Avoid coadministration with a strong or moderate CYP3A inducer and a strong or moderate CYP3A inhibitor

- Select patients for treatment based on the following:

non-small cell lung cancer: Presence of ROS1 rearrangement
Locally advanced or metastatic solid tumors: Presence of a NTRK gene fusion

- Take orally with or without food

Pregnancy level

Forbidden

-This drug can harm a developing fetus.

-Verify negative pregnancy status in females of reproductive potential prior to initiating therapy.

-If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

-Advise female patients of reproductive potential to use effective contraception during therapy and for at least 5 weeks after.

-Advise male patients with female partners of reproductive potential to use effective contraception during therapy and for 3 months after.

Breast feeding warning

-The effects in the nursing infant are unknown.
-Because of the potential for adverse reactions in breastfed infants from this drug, advise lactating women to discontinue breastfeeding during therapy and for 7 days after.

Drug information of Entrectinib