Introduction
Ceritinib is an oral, small molecule tyrosine kinase inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). It represents a second-generation ALK inhibitor developed to overcome resistance that may develop with first-generation ALK inhibitors like crizotinib.
Mechanism of Action
Ceritinib potently inhibits anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase that contributes to cancer cell proliferation and survival when aberrantly activated. The drug targets ALK fusion proteins, including EML4-ALK, with approximately 20-fold greater potency than crizotinib. Ceritinib also demonstrates activity against insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1, though its primary therapeutic effect is mediated through ALK inhibition.
Indications
- Treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib
- First-line treatment of patients with ALK-positive metastatic NSCLC (FDA-approved based on ASCEND-4 trial)
Dosage and Administration
Standard dosing: 750 mg orally once daily on an empty stomach (at least 1 hour before or 2 hours after a meal) Dose modifications: Required for management of adverse reactions- First dose reduction: 600 mg daily
- Second dose reduction: 450 mg daily
- Hepatic impairment: Reduce dose in severe impairment
- Renal impairment: No specific recommendation for mild to moderate impairment; use with caution in severe impairment
- Pediatric: Safety and effectiveness not established
- Geriatric: No specific dose adjustment required
Pharmacokinetics
Absorption: Time to peak concentration: 4-6 hours; high-fat meal increases exposure by 73% Distribution: Volume of distribution: 4,110 L; protein binding: 97% Metabolism: Primarily hepatic via CYP3A4 Elimination: Half-life: 41 hours; fecal excretion (92%, 68% as unchanged drug); renal excretion (1.3%)Contraindications
- Hypersensitivity to ceritinib or any component of the formulation
Warnings and Precautions
Severe GI toxicity: Diarrhea, nausea, vomiting, and abdominal pain may require dose interruption/reduction Hepatotoxicity: Monitor liver function tests; may require dose modification or discontinuation Pneumonitis: Interstitial lung disease/pneumonitis reported; permanently discontinue for treatment-related pneumonitis QT interval prolongation: Monitor ECG and electrolytes; may require dose modification Hyperglycemia: May exacerbate or precipitate diabetes; monitor blood glucose Bradycardia: May cause symptomatic bradycardia; monitor heart rate and blood pressure Pancreatitis: Elevated amylase and lipase reported; monitor pancreatic enzymes Embryo-fetal toxicity: Can cause fetal harm; advise effective contraceptionDrug Interactions
Strong CYP3A inhibitors: Avoid concomitant use (e.g., ketoconazole, ritonavir, clarithromycin) - may increase ceritinib exposure Strong CYP3A inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) - may decrease ceritinib exposure Gastric acid reducing agents: Avoid concomitant proton pump inhibitors; separate H2-receptor antagonists and antacids by several hours QT-prolonging drugs: Use with caution with other drugs that prolong QT intervalAdverse Effects
Very common (≥20%): Diarrhea (86%), nausea (80%), vomiting (60%), abdominal pain (54%), fatigue (52%), decreased appetite (34%), constipation (29%) Common (5-20%): Rash, back pain, dyspnea, cough, dizziness, headache, insomnia, peripheral edema Serious: Hepatotoxicity (11%), pneumonitis (4%), QT prolongation (3%), hyperglycemia (13%), bradycardia (6%)Monitoring Parameters
- Liver function tests (ALT, AST, bilirubin) every 2 weeks for first 2 months, then monthly
- ECG and electrolytes at baseline and periodically during treatment
- Fasting blood glucose at baseline and periodically during treatment
- Amylase and lipase at baseline and periodically during treatment
- Complete blood count with differential
- Weight and nutritional status
- Signs/symptoms of pneumonitis, GI toxicity, and bradycardia
Patient Education
- Take on an empty stomach (1 hour before or 2 hours after meals)
- Do not crush or dissolve capsules
- Report persistent diarrhea, nausea, vomiting, or abdominal pain
- Immediately report new or worsening respiratory symptoms
- Monitor for signs of liver problems (jaundice, dark urine, fatigue)
- Inform all healthcare providers about ceritinib use
- Use effective contraception during treatment and for several months after
- Avoid grapefruit and grapefruit juice during treatment
- Keep all scheduled appointments for monitoring tests
References
1. FDA Prescribing Information: Zykadia (ceritinib) 2. Shaw AT, Kim TM, Crinò L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;18(7):874-886. 3. Soria JC, Tan DSW, Chiari R, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet. 2017;389(10072):917-929. 4. Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov. 2014;4(6):662-673. 5. NCCN Guidelines: Non-Small Cell Lung Cancer. Version 3.2023.