Usage
Tepotinib is prescribed for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. It is classified as a kinase inhibitor, specifically a MET inhibitor. Tepotinib works by selectively inhibiting the c-MET receptor tyrosine kinase, thereby disrupting downstream signaling pathways involved in tumor growth, survival, and metastasis in cancers with these specific genetic alterations.
Alternate Names
Tepotinib is also known by the brand name Tepmetko.
How It Works
Pharmacodynamics: Tepotinib exerts its anti-tumor effects by selectively targeting the c-MET receptor tyrosine kinase, which is often dysregulated in certain types of cancer. By inhibiting c-MET, Tepotinib blocks the activation of downstream signaling pathways that promote tumor cell proliferation, survival, and metastasis.
Pharmacokinetics:
- Absorption: Tepotinib is administered orally and is absorbed with a median Tmax of 4 to 6 hours when taken with food.
- Metabolism: Tepotinib is primarily metabolized in the liver via CYP3A4, with minor contributions from CYP1A2 and CYP2C8.
- Elimination: Tepotinib is predominantly eliminated via feces (approximately 84%), with a smaller fraction excreted in urine (approximately 4%). The effective half-life is around 32 hours, resulting in a median accumulation of 2.5-fold for Cmax and 3.3-fold for AUC0-24h with multiple daily dosing.
Mode of Action: Tepotinib binds to the intracellular ATP-binding site of the c-MET receptor, preventing its autophosphorylation and subsequent activation. This inhibition disrupts downstream signaling cascades, including the RAS-MAPK and PI3K-AKT pathways, leading to reduced tumor cell growth and survival.
Dosage
Standard Dosage
Adults:
The recommended dose of Tepotinib is 450 mg (two 225 mg tablets) taken orally once daily with food. Treatment continues until disease progression or unacceptable toxicity.
Children:
The safety and efficacy of Tepotinib in pediatric patients below 18 years of age have not been established.
Special Cases:
- Elderly Patients: No dose adjustment is necessary in patients aged 65 years and above.
- Patients with Renal Impairment: No dose adjustment is recommended for mild or moderate renal impairment. The use of Tepotinib in patients with severe renal impairment has not been studied.
- Patients with Hepatic Dysfunction: No dose adjustment is recommended for mild or moderate hepatic impairment. The use of Tepotinib in patients with severe hepatic impairment is not recommended.
- Patients with Comorbid Conditions: Careful monitoring is required in patients with pre-existing liver or lung conditions.
Clinical Use Cases
The clinical use of Tepotinib is currently limited to the treatment of metastatic NSCLC with MET exon 14 skipping alterations. It is not indicated for intubation, surgical procedures, mechanical ventilation, intensive care unit (ICU) use, or emergency situations.
Dosage Adjustments
Dose reductions to 225 mg once daily may be necessary for managing adverse reactions. Treatment may be temporarily interrupted or permanently discontinued depending on the severity and persistence of adverse reactions.
Side Effects
Common Side Effects:
Peripheral edema, nausea, diarrhea, constipation, vomiting, fatigue, decreased appetite, abdominal pain, musculoskeletal pain, increased creatinine, elevated liver enzymes (ALT, AST), hypoalbuminemia.
Rare but Serious Side Effects:
Interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, severe allergic reactions.
Long-Term Effects:
Long-term effects of Tepotinib are not yet fully characterized due to its relatively recent approval. Continued monitoring for potential long-term toxicities is essential.
Adverse Drug Reactions (ADR):
ILD/pneumonitis and hepatotoxicity are clinically significant ADRs requiring immediate intervention, including discontinuation of treatment.
Contraindications
Hypersensitivity to tepotinib or any of its components.
Drug Interactions
- CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, St. John’s Wort) may decrease tepotinib exposure and should be avoided.
- CYP3A4/P-gp Inhibitors: Dual strong CYP3A4 and P-gp inhibitors (e.g., itraconazole, ketoconazole) can significantly increase tepotinib exposure and risk of adverse events and should be avoided.
- P-gp Substrates: Tepotinib may increase the serum concentrations of P-gp substrates (e.g., digoxin, dabigatran). Careful monitoring is necessary when co-administering such medications.
- BCRP Substrates: Tepotinib may increase the serum concentrations of BCRP substrates. Monitoring the clinical effect of these drugs is recommended during co-administration.
- Metformin: Tepotinib may alter metformin exposure. Clinical monitoring of metformin effects is advised.
Pregnancy and Breastfeeding
- Pregnancy: Tepotinib is contraindicated during pregnancy due to its potential for teratogenicity. Females of reproductive potential should use effective contraception during treatment and for at least 1 week after the last dose. Male patients with female partners of reproductive potential should also use effective contraception.
- Breastfeeding: Tepotinib is contraindicated during breastfeeding. It is not known if tepotinib is excreted in human milk. Breastfeeding should be discontinued during treatment and for at least one week after the last dose.
Drug Profile Summary
- Mechanism of Action: MET inhibitor, targets c-MET receptor tyrosine kinase.
- Side Effects: Peripheral edema, nausea, diarrhea, fatigue, ILD/pneumonitis (rare but serious).
- Contraindications: Hypersensitivity, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inducers/inhibitors, P-gp substrates, BCRP substrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 450 mg orally once daily with food.
- Monitoring Parameters: Liver function tests (LFTs), renal function, pulmonary function, complete blood count (CBC), electrolytes.
Popular Combinations
Currently, there are no established popular drug combinations used routinely with tepotinib. Clinical trials are ongoing to evaluate potential combination therapies.
Precautions
- Assess METex14 skipping alterations status before initiating treatment.
- Monitor for pulmonary symptoms indicative of ILD/pneumonitis.
- Monitor LFTs regularly.
- Monitor for renal dysfunction.
- Patients should avoid driving or operating machinery if they experience fatigue or asthenia.
- Assess pregnancy status in females of reproductive potential before treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tepotinib?
A: 450 mg orally once daily with food for adults. Dose reductions may be required to manage adverse reactions. Not established for pediatric patients.
Q2: What is the mechanism of action of Tepotinib?
A: Tepotinib is a selective c-MET inhibitor, blocking the activation of downstream signaling pathways involved in tumor growth and survival.
Q3: What are the most common side effects of Tepotinib?
A: Peripheral edema, nausea, diarrhea, fatigue, and musculoskeletal pain.
Q4: What are the serious side effects of Tepotinib?
A: ILD/pneumonitis and hepatotoxicity are rare but serious side effects that require immediate attention.
Q5: Can Tepotinib be used during pregnancy or breastfeeding?
A: No, Tepotinib is contraindicated during pregnancy and breastfeeding due to potential harm to the fetus or infant.
Q6: What are the important drug interactions with Tepotinib?
A: Tepotinib interacts with strong CYP3A4 inducers and inhibitors, P-gp substrates, BCRP substrates, and metformin.
Q7: What are the key monitoring parameters for patients on Tepotinib?
A: LFTs, renal function, pulmonary function, CBC, and electrolytes.
Q8: How should a missed dose of Tepotinib be handled?
A: If a dose is missed within 8 hours of the next scheduled dose, skip the missed dose and take the next dose at the regular time. Do not double the dose.
Q9: What is the duration of therapy for Tepotinib?
A: Treatment continues until disease progression or unacceptable toxicity occurs.
