Lenvatinib
Lenvatinib
Generic Name
Lenvatinib
Mechanism
- Selective inhibitor of multiple receptor tyrosine kinases (RTKs) involved in tumor angiogenesis and growth:
- Vascular endothelial growth factors VEGFR‑1, 2, 3
- Platelet‑derived growth factor receptor PDGFR‑α
- Fibroblast growth factor receptors FGFR‑1–4
- c‑Kit and RET signaling pathways
- By blocking these RTKs, Lenvatinib suppresses tumor neovascularization, reduces tumor cell proliferation, and induces apoptosis.
Pharmacokinetics
- Absorption: Oral bioavailability ~44 %; peak plasma concentrations 3–5 h post‑dose.
- Distribution: Highly protein‑bound (>95 %); volume of distribution ≈ 370 L.
- Metabolism: Predominantly via CYP3A4/5; minor role of CYP2D6, CYP2C19, and CYP2C9.
- Elimination: Primarily renal (≈ 50 %) and biliary/fecal routes; mean terminal half‑life 10–12 h.
- Drug–drug interactions: Potentiated by strong CYP3A4 inhibitors/inducers; concurrent use with potent anti‑platelet agents (e.g., aspirin) increases bleeding risk.
Indications
- Radio‑iodine refractory differentiated thyroid carcinoma** → FDA‑approved first‑line therapy.
- Locally advanced or metastatic hepatocellular carcinoma (HCC) when ≥ 12 mo post‑treatment failure in a Child‑Pugh A liver function setting—often used with TACE or as monotherapy.
- Endometrial cancer * (investigational, part of combination protocols).
- Off‑label use includes certain pituitary adenomas and renal cell carcinoma.
Contraindications
- Contraindications:
- Known hypersensitivity to Lenvatinib or its excipients.
- Severe uncontrolled hypertension (SBP > 180 mm Hg or DBP > 110 mm Hg).
- Warnings:
- Serious cardiovascular events: heart failure, arrhythmias, thromboembolic phenomena.
- Severe hypertension (require ≥2 antihypertensives to maintain at goal).
- Bleeding risk: GI, intracranial, and platelet‑dependent hemorrhage.
- Liver dysfunction: Monitor hepatic enzymes; avoid in decompensated cirrhosis.
- Pregnancy: Category X—teratogenic risk; advise contraception for both sexes.
Dosing
| Indication | Dose & Schedule |
| Radio‑iodine refractory thyroid carcinoma | 24 mg PO once daily (split 12 mg BID if > 100 kg body weight) |
| HCC (first‑line) | Lenvatinib 8 mg PO once daily (24 kg–49 kg: 8 mg; 50 kg–< 75 kg: 12 mg; ≥75 kg: 24 mg) |
| Short course / Bridge therapy | Same as indication‑specific dosing; max 12 wk per cycle. |
• Administration: With or without food; avoid alcohol. Maintain consistent daily timing to avoid peak‑to‑peak variability (Cmax/Dmax).
• Rescue dosing: Slow escalation (starting at 1/4 dose) may mitigate initial hypertension in elderly or CKD patients.
• Re‑dosing / Dose interruption: For grade ≥ 3 AEs, temporarily hold until resolution to grade ≤ 1, then resume at lower dose.
Adverse Effects
- Common (> 20 %)
- Hypertension
- Lymphopenia
- Fatigue
- Decreased appetite
- Nausea/vomiting
- Diarrhea/constipation
- Palmar‑plantar erythrodysesthesia
- Weight loss
- Serious (≥ 3 %)
- Grade 3‑4 hypertension (≥180/110 mm Hg), requiring aggressive control
- Proteinuria (≥ grade 2) → monitor urine dipsticks bi‑weekly
- Cardiac events (heart failure, arrhythmias)
- Bleeding (GI or intracranial)
- Hepatic dysfunction (grade ≥ 3 transaminitis)
- Thromboembolism
- Severe infections due to lymphopenia
Monitoring
| Parameter | Frequency | Rationale |
| Blood pressure | Daily at home; clinic 2×/week initially | Prevent hypertensive crises |
| Complete blood count (CBC) & differential | Every 2–4 weeks | Detect lymphopenia, thrombocytopenia |
| Serum creatinine & eGFR | Bi‑weekly first month, then monthly | Renal clearance & drug accumulation |
| LFTs (AST, ALT, bilirubin, ALT) | Bi‑weekly first month, then monthly | Hepatotoxicity monitoring |
| Urinalysis for proteinuria | 2×/month | Early detection of renal toxicity |
| ECG (baseline, every 3 months) | Baseline & when symptomatic | Cardiac toxicity risk |
| Pregnancy test (males/females, baseline) | Baseline & periodical | Teratogenic risk |
• Dose adjustment criteria:
• Hypertension: Re‑dose at 50 % if BP not controlled.
• Proteinuria: Hold until <30 mg/day; resume at same dose if 3× ULN; reduce dose if recurrent.
Clinical Pearls
- “Split‑dose strategy”: For patients over 100 kg or with severe GI intolerance, dividing the daily dose improves tolerability but does not compromise efficacy because of Lenvatinib’s low hepatic metabolism.
- “Hypertension first, then cardio”: Tight BP control before initiating Lenvatinib dramatically reduces serious cardiovascular events; ACE‑I/ARB first line, add diuretics as needed.
- “Beware of drug‑induced myelosuppression”: A trend for lymphopenia can predispose to opportunistic infections; consider prophylactic measures in high‑risk patients (e.g., prophylactic antivirals).
- “Radiographic assessment”: Use RECIST v1.1 with optional Choi criteria; early tumor flare may mis‑represent response if evaluated solely on size changes.
- “Pregnancy and lactation”: Strict counseling needed—Lenvatinib has high teratogenic liability; both partners should avoid pregnancy during therapy and for 6 months post‑discontinuation.
- “Drug–drug interactions": When co‑administered with CYP3A4 inducers (e.g., rifampin), reduce dose by ~50%; inducers of CYP2C9 and CYP2C19 can increase plasma concentrations as well.
> Quick Ref‑Point: *Lenvatinib – oral multitargeted RTK inhibitor; first‑line for iodine‑refractory thyroid cancer and advanced HCC; watch for HTN, proteinuria, and bleeding.*