Zykadia - Drug Monograph

Introduction

Zykadia (ceritinib) is an oral, small-molecule tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK). It is approved for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC), including as a first-line option and after progression on or intolerance to crizotinib. Its clinical relevance lies in providing an effective targeted therapy for a molecularly defined subset of NSCLC, with activity against several ALK resistance mutations that emerge after first-generation ALK inhibitor therapy.

Drug Class and Overview

• Class: Tyrosine kinase inhibitor (TKI); second-generation ALK inhibitor.
• Related agents: Crizotinib (first-generation ALK/ROS1 inhibitor), alectinib and brigatinib (second-generation ALK inhibitors), lorlatinib (third-generation ALK/ROS1 inhibitor).
• Distinguishing features: Ceritinib inhibits ALK with greater potency than crizotinib and retains activity against many crizotinib-resistant ALK mutations (e.g., L1196M, G1269A, I1171T, S1206Y). It also has activity against ROS1 and IGF-1R. Compared with alectinib and brigatinib, ceritinib has a higher rate of gastrointestinal toxicity and is generally reserved for patients who cannot tolerate or have disease progression on other ALK inhibitors.

Mechanism of Action

Ceritinib binds to the ATP-binding site of the ALK tyrosine kinase and inhibits its phosphorylation and downstream signaling (including STAT3, PI3K/AKT, and RAS/RAF/MEK/ERK pathways). In ALK-rearranged NSCLC, chromosomal translocations (most commonly EML4-ALK) produce a constitutively active fusion oncoprotein that drives tumor proliferation and survival. By blocking ALK activity, ceritinib halts downstream oncogenic signaling and induces tumor cell apoptosis. Ceritinib also inhibits ROS1 and IGF-1R, which may contribute to its activity in selected tumors.

Indications

• Treatment of adult patients with ALK-positive metastatic NSCLC, as detected by an FDA-approved companion diagnostic test.
• Use is supported in:
• First-line therapy for ALK-positive metastatic NSCLC.
• Patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.
• Inclusion in major oncology guidelines (e.g., NCCN) as a recommended option for ALK-positive NSCLC, particularly when other second-generation ALK inhibitors are not available or tolerated.

Dosage and Administration

• Recommended adult dose: 450 mg orally once daily, taken with food (the original 750 mg fasted dose was revised to 450 mg with food to improve gastrointestinal tolerability while maintaining comparable exposure).
• Route: Oral; swallow capsules whole; do not crush or chew.
• Duration: Continue until disease progression or unacceptable toxicity.
• Renal impairment: No initial dose adjustment required for mild to moderate impairment; use with caution in severe impairment (limited data).
• Hepatic impairment: No initial dose adjustment required for mild impairment; use with caution in moderate to severe impairment (limited data).
• Pediatric: Safety and efficacy not established.
• Geriatric: No specific dose adjustment based on age alone; monitor for increased toxicity.
• Pregnancy/Lactation: May cause fetal harm based on animal data; effective contraception is recommended during treatment and for a defined period after the last dose. Breastfeeding is not recommended during treatment.

Pharmacokinetics

• Absorption: Oral bioavailability is increased when taken with food (approximately 1.5- to 2-fold higher exposure with a meal compared with the fasted state), which is why the labeled dose is taken with food.
• Distribution: Highly protein-bound (>97%); large volume of distribution.
• Metabolism: Primarily hepatic via CYP3A4, with minor contributions from CYP2C9 and CYP3A5.
• Elimination: Mainly fecal (biliary excretion) with a smaller renal component.
• Half-life: Approximately 40–41 hours, supporting once-daily dosing.
• Time to steady state: Approximately 3 weeks.

Contraindications

• None listed as absolute contraindications in the FDA prescribing information; however, ceritinib is contraindicated in patients with known severe hypersensitivity to ceritinib or any component of the formulation.

Warnings and Precautions

• Hepatotoxicity: Drug-induced hepatotoxicity, including grade 3–4 transaminase elevations, has been reported. Monitor liver function tests (ALT, AST, total bilirubin) every 2 weeks during the first 2 months, then monthly. Withhold and reduce dose or permanently discontinue based on severity.
• Interstitial lung disease (ILD)/Pneumonitis: Severe, life-threatening, or fatal ILD/pneumonitis has been observed. Evaluate any new or worsening pulmonary symptoms; withhold ceritinib if ILD is suspected and permanently discontinue if treatment-related ILD is confirmed.
• QT interval prolongation: Ceritinib can cause concentration-dependent QTc prolongation. Avoid use in patients with congenital long QT syndrome. Monitor ECG and electrolytes (especially potassium, magnesium) in patients with congestive heart failure, bradyarrhythmias, or those taking other QT-prolonging drugs. Withhold or reduce dose for QTc ≥500 ms or a ≥60 ms increase from baseline.
• Bradycardia: Symptomatic bradycardia has been reported. Avoid coadministration with other bradycardia-inducing agents when possible; monitor heart rate and blood pressure regularly.
• Hyperglycemia: New or worsening hyperglycemia has been reported; monitor fasting glucose, particularly in patients with diabetes or on corticosteroids.
• Gastrointestinal toxicity: Nausea, vomiting, diarrhea, and abdominal pain are very common; prophylactic antiemetics and antidiarrheals are often required.
• Pancreatic toxicity: Elevations in lipase and amylase have been reported; monitor and evaluate for pancreatitis if symptoms develop.
• Embryo-fetal toxicity: Based on mechanism and animal data, ceritinib may cause fetal harm.

Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit juice): Significantly increase ceritinib exposure. Avoid concomitant use; if unavoidable, reduce the ceritinib dose by approximately one-third and monitor closely.
• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort): Significantly decrease ceritinib exposure and may reduce efficacy. Avoid concomitant use.
• CYP3A4 substrates with narrow therapeutic indices (e.g., cyclosporine, tacrolimus, ergot alkaloids, fentanyl, quinidine): Ceritinib may increase their exposure; use with caution and consider dose reduction of the substrate.
• QT-prolonging agents (e.g., antiarrhythmics, fluoroquinolones, certain antipsychotics, ondansetron): Additive QT prolongation risk; monitor ECG and electrolytes.
• Bradycardia-inducing agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin): Additive risk of symptomatic bradycardia.
• Acid-reducing agents: Proton pump inhibitors, H2 antagonists, and antacids may alter ceritinib solubility and absorption; avoid PPIs and H2 blockers if possible, or use antacids with appropriate timing separation.

Adverse Effects

Very common (≥25%):

• Diarrhea, nausea, vomiting, abdominal pain
• Fatigue/asthenia
• Decreased appetite
• Constipation
• Elevated transaminases (ALT, AST)

Common (10–25%):

• Headache
• Rash
• Anemia, leukopenia
• Hyperglycemia
• Hypophosphatemia
• Elevated creatinine
• Cough, dyspnea
• QT prolongation
• Bradycardia

Serious/rare but clinically important:

• Interstitial lung disease/pneumonitis
• Severe hepatotoxicity
• Symptomatic bradycardia
• Pancreatitis
• Severe hyperglycemia
• QT prolongation with torsades de pointes (rare)

Monitoring Parameters

• Hepatic panel (ALT, AST, total bilirubin): every 2 weeks for the first 2 months, then monthly.
• ECG (QTc interval): baseline and periodically, especially in patients with risk factors or on concomitant QT-prolonging drugs.
• Electrolytes: potassium, magnesium, calcium at baseline and as clinically indicated.
• Fasting glucose: baseline and periodically, particularly in diabetic patients.
• Lipase/amylase: baseline and as clinically indicated.
• Heart rate and blood pressure: at each visit.
• Pulmonary symptoms: assess for cough, dyspnea, fever, or hypoxia at each visit.
• Renal function: serum creatinine periodically.
• Complete blood count: periodically.

Patient Education

• Take ceritinib once daily with food at approximately the same time each day; swallow capsules whole.
• Do not drink grapefruit juice or eat grapefruit, and avoid St. John's wort.
• Report any new or worsening nausea, vomiting, diarrhea, abdominal pain, or dehydration to your clinician; prophylactic antiemetics and antidiarrheals may be prescribed.
• Report any new cough, shortness of breath, fever, or chest discomfort immediately (possible lung inflammation).
• Report yellowing of the skin or eyes, dark urine, severe fatigue, or right-sided abdominal pain (possible liver toxicity).
• Report dizziness, fainting, or unusually slow heartbeats (possible bradycardia or QT prolongation).
• Use effective contraception during treatment and for at least 6 months after the last dose; do not breastfeed during treatment.
• Inform all healthcare providers about all medications, including over-the-counter drugs and supplements.
• Do not start or stop any medication without consulting your oncology team.

Clinical Pearls

1. Take with food: The 450 mg with-food dose produces similar exposure to the original 750 mg fasted dose but with markedly improved GI tolerability — this is a high-yield counseling point.
2. CYP3A4 is the key metabolic pathway: Always screen for drug interactions with strong CYP3A4 inhibitors and inducers, which can dramatically alter ceritinib exposure.
3. Pneumonitis is a "stop and think" toxicity: Any new pulmonary symptoms should prompt immediate evaluation for ILD, as this is a potentially fatal adverse effect requiring permanent discontinuation if confirmed.
4. QT and bradycardia are paired concerns: Ceritinib can prolong QT and slow heart rate; baseline ECG and electrolyte optimization are essential, especially in patients with cardiac risk factors.
5. Hepatotoxicity is dose-limiting in many patients: Routine LFT monitoring every 2 weeks for the first 2 months catches transaminase elevations early, allowing dose holds before severe injury develops.
6. Companion diagnostic is mandatory: ALK rearrangement must be confirmed by an FDA-approved test (e.g., FISH, IHC, or NGS) before initiating therapy.

References

1. U.S. Food and Drug Administration. Zykadia (ceritinib) Prescribing Information. Novartis Pharmaceuticals Corporation.
2. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer (current version).
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.
4. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014.
5. Gainor JF, Dardaei L, Yoda S, et al. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Cancer Discov. 2016.
6. Brunton LL, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. McGraw-Hill.
7. Katzung BG, Vanderah TW, eds. Basic and Clinical Pharmacology. 15th ed. McGraw-Hill.
8. Lexicomp Online. Ceritinib: Drug Information. Wolters Kluwer Clinical Drug Information.
9. American Society of Clinical Oncology (ASCO). Guidelines and educational resources on targeted therapy in NSCLC.
10. World Health Organization (WHO). Essential Medicines List and related oncology resources.