Usage
Lenvatinib is prescribed for the treatment of various cancers, including:
- Differentiated Thyroid Cancer (DTC): Specifically, locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
- Advanced Renal Cell Carcinoma (RCC): In combination with everolimus, following one prior anti-angiogenic therapy. It is also used as a monotherapy.
- Unresectable Hepatocellular Carcinoma (HCC): As a first-line treatment.
- Advanced Endometrial Carcinoma: In combination with pembrolizumab, for patients whose disease has progressed following prior systemic therapy and who are not candidates for curative surgery or radiation. This applies to cases that are not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
Pharmacological Classification: Kinase inhibitor, specifically a multi-kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), platelet-derived growth factor receptor alpha (PDGFRα), RET, and KIT.
Mechanism of Action: Lenvatinib inhibits the activity of multiple receptor tyrosine kinases (RTKs) involved in tumor angiogenesis and growth. By blocking these RTKs, lenvatinib reduces tumor vascularization and slows tumor growth and proliferation.
Alternate Names
Generic Name: Lenvatinib
Brand Names: Lenvima, Kisplyx
How It Works
Pharmacodynamics: Lenvatinib exerts its anti-tumor effects by inhibiting multiple RTKs. This inhibition leads to a reduction in angiogenesis (formation of new blood vessels), thereby limiting the supply of oxygen and nutrients to the tumor. It also disrupts signaling pathways crucial for tumor cell growth and proliferation.
Pharmacokinetics:
- Absorption: Lenvatinib is orally administered and reaches peak plasma concentrations within 1 to 4 hours. Food does not significantly affect absorption.
- Metabolism: Primarily metabolized in the liver by CYP3A4.
- Elimination: Excreted mainly through the feces (approximately two-thirds), with the remainder eliminated in the urine. The elimination half-life is around 28 hours.
Mode of Action: Lenvatinib competitively binds to the ATP-binding pockets of its target RTKs, preventing their activation and downstream signaling.
Receptor Binding/Enzyme Inhibition: Lenvatinib inhibits the kinase activity of VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT.
Elimination Pathways: Predominantly hepatic metabolism (CYP3A4) followed by fecal excretion.
Dosage
Standard Dosage
Adults:
- DTC: 24 mg orally once daily.
- RCC (with everolimus): 18 mg orally once daily with everolimus 5 mg orally once daily.
- RCC (monotherapy): 24 mg orally once daily.
- HCC: Weight-based dosing: <60 kg: 8 mg orally daily; ≥60 kg: 12 mg orally daily.
- Endometrial Carcinoma (with pembrolizumab): 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks.
Children: The safety and efficacy of lenvatinib in pediatric patients have not been established. Off-label use has been reported in some cases, but no standardized dosing guidelines exist.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended for elderly patients, but caution is advised due to potential increased sensitivity to adverse effects, especially in patients 75 years or older. Close monitoring is recommended.
- Patients with Renal Impairment: Dose adjustment is required for severe renal impairment (creatinine clearance <30 mL/min): DTC: 14 mg orally daily; RCC and Endometrial Carcinoma: 10 mg orally daily. No adjustment needed for mild or moderate impairment.
- Patients with Hepatic Dysfunction: For severe hepatic impairment (Child-Pugh C): DTC: 14 mg orally daily; RCC and Endometrial Carcinoma: 10 mg orally daily. No adjustment needed for mild or moderate impairment.
- Patients with Comorbid Conditions: Careful consideration is required for patients with pre-existing cardiovascular disease, hypertension, or other relevant comorbidities. Close monitoring is essential.
Clinical Use Cases
Lenvatinib’s clinical use is primarily focused on the cancer types listed above. It is not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose modifications are based on individual tolerability and the occurrence of adverse events. Dose interruptions, reductions, or discontinuation may be necessary. Consult specific guidelines and tables for recommended adjustments for various adverse reactions.
Side Effects
Common Side Effects:
Hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, nausea, vomiting, stomatitis, headache, and rash.
Rare but Serious Side Effects:
Hepatic failure, hepatic encephalopathy, cardiac dysfunction, arterial thromboembolism, gastrointestinal perforation, renal failure, QT interval prolongation, posterior reversible encephalopathy syndrome (PRES), fistula formation, and severe bleeding.
Contraindications
- Hypersensitivity to lenvatinib or any of its components.
- Breastfeeding.
- Pregnancy (unless clearly necessary and after careful consideration of risks and benefits).
Drug Interactions
Lenvatinib interacts with numerous medications, including those metabolized by CYP3A4 (inducers and inhibitors), QT-prolonging drugs, and medications affecting bleeding risk. Consult a comprehensive drug interaction resource for details. Some notable interactions include:
- CYP3A4 Inhibitors: May increase lenvatinib levels.
- CYP3A4 Inducers: May decrease lenvatinib levels.
- QT-prolonging Drugs: Increased risk of arrhythmias.
- Anticoagulants/Antiplatelets: Increased bleeding risk.
Interactions with food (e.g., grapefruit juice) and lifestyle factors (e.g., smoking) are also possible.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Lenvatinib is contraindicated during pregnancy due to the risk of fetal harm (embryotoxicity, fetotoxicity, teratogenicity). Effective contraception is essential during treatment and for at least one month after discontinuation.
- Breastfeeding: Lenvatinib is contraindicated during breastfeeding. It is recommended to discontinue breastfeeding during treatment and for at least one week after the last dose.
Drug Profile Summary
- Mechanism of Action: Multi-kinase inhibitor targeting VEGFR1-3, FGFR1-4, PDGFRα, RET, and KIT, leading to inhibition of angiogenesis and tumor growth.
- Side Effects: Hypertension, fatigue, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, proteinuria. Serious side effects include hepatic failure, cardiac dysfunction, and bleeding.
- Contraindications: Hypersensitivity, breastfeeding, pregnancy.
- Drug Interactions: Numerous drug interactions, including CYP3A4 interactions and effects on QT interval.
- Pregnancy & Breastfeeding: Contraindicated in both.
- Dosage: Variable depending on indication and patient characteristics. See detailed dosage guidelines above.
- Monitoring Parameters: Blood pressure, liver function tests, renal function tests, thyroid function tests, complete blood counts, and electrocardiogram (ECG).
Popular Combinations
- Lenvatinib + Everolimus: For advanced RCC.
- Lenvatinib + Pembrolizumab: For advanced endometrial carcinoma.
Precautions
- General Precautions: Monitor blood pressure, liver function, renal function, and thyroid function closely. Assess for signs of bleeding, gastrointestinal perforation, and cardiac dysfunction.
- Specific Populations: See special cases under dosage.
- Lifestyle Considerations: Advise patients to avoid alcohol and manage other lifestyle factors that may exacerbate side effects or interact with lenvatinib.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lenvatinib?
A: The dosage varies depending on the indication and patient factors. See the detailed dosage guidelines above.
Q2: What are the most common side effects of Lenvatinib?
A: Hypertension, fatigue, diarrhea, decreased appetite, and palmar-plantar erythrodysesthesia syndrome.
Q3: How should hypertension be managed in patients taking Lenvatinib?
A: Blood pressure should be well-controlled before starting lenvatinib. Close monitoring is essential, and antihypertensive therapy should be initiated or adjusted as needed.
Q4: What are the contraindications for Lenvatinib?
A: Hypersensitivity to lenvatinib, breastfeeding, and pregnancy.
Q5: Does Lenvatinib interact with other medications?
A: Yes, lenvatinib has numerous drug interactions. Consult a comprehensive drug interaction resource and the prescribing information for details.
Q6: Can Lenvatinib be used in patients with renal or hepatic impairment?
A: Dose adjustments are necessary for patients with severe renal or hepatic impairment. No dose adjustment is needed for mild or moderate impairment.
Q7: What monitoring parameters are important for patients on Lenvatinib?
A: Blood pressure, liver function tests, renal function tests, thyroid function tests, complete blood counts, and ECG.
Q8: Are there any specific precautions for elderly patients taking Lenvatinib?
A: Elderly patients, especially those 75 years or older, may be more susceptible to adverse effects and require close monitoring.
Q9: What should be done if a patient misses a dose of Lenvatinib?
A: If a dose is missed and cannot be taken within 12 hours, skip the missed dose and take the next dose at the usual time. Do not double the dose.
