Rozlytrek 200 mg

Indications

• ROS1-positive advanced non-small cell lung cancer
• Solid tumors with neurotrophic tyrosine receptor kinase gene fusion

Dosage

Adults: 600 mg once daily. Dose adjustments may be required for patients with hepatic impairment or those receiving concomitant CYP3A4 inhibitors.

Mechanism of action

Entrectinib acts as an ATP competitor that inhibits tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, TRKC, along with the proto-oncogene tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). This inhibition disrupts downstream signaling pathways including the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and JAK/STAT pathways, which leads to reduced cancer cell proliferation and promotes apoptosis, resulting in tumor shrinkage.

Pharmacodynamics

Entrectinib and its active metabolite suppress multiple pathways that are crucial for cancer cell survival and proliferation. This pharmacodynamic effect shifts the balance towards apoptosis, thereby inhibiting tumor growth and reducing tumor size.

Pharmacokinetics

Entrectinib is administered orally, and its pharmacokinetics are influenced by hepatic and renal function. The drug undergoes metabolism primarily through CYP3A4. Caution is advised when used with CYP3A4 inhibitors, as they can significantly affect drug exposure. The medication's half-life, distribution, and elimination details are not specified but require monitoring of liver function and renal impairment during treatment.

Contra-indications

• Congenital long QT syndrome

Adverse effects

• Alopecia
• Angioedema
• Appetite changes
• Arthralgia
• Arthritis
• Constipation
• Facial paralysis
• Fatigue
• Fever
• Hypersensitivity reactions
• Insomnia
• Muscle weakness
• Nausea
• Pancreatitis
• Photosensitivity reactions
• QT interval prolongation
• Renal impairment
• Skin reactions
• Taste alteration
• Visual impairment
• Vomiting

Interactions

• Severe interactions with azole antifungals (increases exposure)
• Severe interaction with dabrafenib (decreases exposure)
• Severe interaction with St. John's wort (decreases exposure)
• Unknown interaction with dronedarone (increases exposure)
• Unknown interaction with midazolam (increases exposure)
• Unknown interaction with ciclosporin (increases exposure)
• Unknown interaction with cobicistat (increases exposure)
• Unknown interaction with crizotinib (increases exposure)
• Unknown interaction with bosentan (decreases exposure)
• Unknown interaction with benzodiazepines (increases exposure)

Precautions

• Caution in patients with mild hepatic impairment (increased exposure)
• Avoid in moderate or severe hepatic impairment (no information available)
• Caution in patients with renal impairment (no information available)
• Monitor for cutaneous squamous cell carcinoma and new primary melanoma before treatment
• Monitor liver function before treatment and at least monthly during the first six months
• Assess ECG before treatment and periodically afterwards
• Monitor blood creatinine levels as clinically indicated
• Assess left ventricular ejection fraction before initiation
• Monitor for ophthalmologic reactions including uveitis, iridocyclitis, and iritis

Pregnancy

Manufacturer advises to avoid due to toxicity in animal studies.

Breast-feeding

Manufacturer advises to avoid; no information available.

Storage

Store in a cool, dry place away from light.

Formulations

• Entrectinib 100

Mechanism of action

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.

Pharmacodynamics

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.