Mereletinib

Uses

Mereletinib is used for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Mereletinib is also used to associated treatment for these conditions: Metastatic Non-Small Cell Lung Cancer

How Mereletinib works

Mereletinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.

Dosage

Mereletinib dosage

The recommended dose of Mereletinib is 80 mg once a day until disease progression or unacceptable toxicity. Mereletinib can be taken with or without food. If a dose of Mereletinib is missed, do not make up the missed dose and take the next dose as scheduled.

Administration To Patients Who Have Difficulty Swallowing Solids: Disperse tablet in 60 ml (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 ml to 240 ml (4 to 8 ounces of) water and immediately drink.

If administration via nasogastric tube is required, disperse the tablet as above in 15 ml of non-carbonated water, and then use an additional 15 ml of water to transfer any residues to the syringe. The resulting 30 ml liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 ml).

Side Effects

Common side effects are Interstitial Lung Disease or Pneumonitis, QTc Interval Prolongation, Cardiomyopathy, Keratitis

Toxicity

Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.3% of treated patients with 0.5% of these being fatal. There is also a change of QTc interval prolongation; electrocardiogram and electrolytes should be monitored in patients with a history or predisposition for QTc prolongation. Cardiomyopathy occurred in 1.4% of patients, therefore left ventricular ejection fraction (LVEF) should be measured at baseline and then every 3 months during treatment. Mereletinib can cause embryo-fetal toxicity, requiring female patients to take effective birth control during therapy and for 6 weeks after final dose.

Interaction

Strong CYP3A4 Inducers: If concurrent use is unavoidable, increase Mereletinib dosage to 160 mg daily when coadministering with a strong CYP3A inducer. Resume Mereletinib at 80 mg 3 weeks after discontinuation of the strong CYP3A4 inducer

Food Interaction

• Avoid St. John's Wort. This herb induces the CYP3A metabolism of osimertinib, and therefore, dose adjustments are necessary if they must be co-administered.
• Take at the same time every day.
• Take with or without food.

Mereletinib Drug Interaction

Major: doxorubicinModerate: suvorexantUnknown: paclitaxel protein-bound, charcoal, contained in alcoholic beverages , RHO Immunoglobulin , pramoxine/zinc oxide topical, multivitamin with minerals, aspirin, diphenhydramine, dapagliflozin, atorvastatin, omega-3 polyunsaturated fatty acids, acetaminophen, vitamin a topical, multivitamin, pyridoxine, ascorbic acid, cholecalciferol, menaquinone

Mereletinib Disease Interaction

Major: cardiomyopathy, dermatologic toxicities, ocular disorders, pulmonary toxicity, QT prolongationModerate: renal/liver impairment

Volume of Distribution

The mean volume of distribution at steady state is 986 L.

Elimination Route

The median time to Cmax was found to be 6 hours.

Half Life

The population estimated mean half-life is 48 hours.

Clearance

Oral clearance is 14.2 L/hr.

Elimination Route

Mereletinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.

Pregnancy & Breastfeeding use

Use in Pregnancy: There are no or limited amount of data from the use of Mereletinib in pregnant women. Studies in animals have shown reproductive toxicity. Based on its mechanism of action and preclinical data, Mereletinib may cause foetal harm when administered to a pregnant woman. Administration of osimertinib to pregnant rats was associated with embryolethality, reduced foetal growth and neonatal death at exposures similar to what is expected in humans. Mereletinib is not recommended during pregnancy and in women of childbearing potential not using contraception.

Use in Lactation: It is not known whether osimertinib or its metabolites are excreted in human milk. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death. There is insufficient information on the excretion of osimertinib or its metabolites in animal milk. A risk to the suckling child cannot be excluded. Breast-feeding should discontinue during treatment with Mereletinib.

Fertility: There are no data on the effect of Mereletinib on human fertility. Results from animal studies have shown that Mereletinib has effects on male and female reproductive organs and could impair fertility

Storage Condition

Store Mereletinib at room temperature between 20°C to 25°C. Safely throw away medicine that is out of date or that you no longer need. Keep Mereletinib and all medicines out of the reach of children.

Innovators Monograph

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