Usage
- Ceritinib is prescribed for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. A diagnostic test should be performed to confirm ALK-positive status.
- Pharmacological classification: Ceritinib is an antineoplastic agent, specifically a kinase inhibitor.
- Mechanism of action: Ceritinib inhibits ALK tyrosine kinase activity, disrupting the signaling pathways involved in the growth and survival of cancer cells.
Alternate Names
How It Works
- Pharmacodynamics: Ceritinib selectively targets and inhibits ALK, thereby hindering tumor growth and potentially inducing apoptosis (programmed cell death) in ALK-positive cancer cells.
- Pharmacokinetics:
- Absorption: Ceritinib is administered orally and its bioavailability is increased when taken with food.
- Metabolism: Primarily metabolized by the liver, specifically by CYP3A4 enzyme.
- Elimination: Predominantly eliminated via hepatic routes (feces), with negligible renal excretion.
- Mode of action: Ceritinib binds to and inhibits the ALK receptor tyrosine kinase, thus blocking downstream signaling pathways that promote cancer cell proliferation and survival. This leads to cell cycle arrest and ultimately cell death in ALK-positive tumor cells.
- Receptor binding/Enzyme inhibition: Ceritinib exhibits potent and selective inhibition of ALK. It also inhibits other kinases to a lesser extent, including insulin-like growth factor 1 receptor (IGF-1R) and ROS1 (c-ros oncogene 1, receptor tyrosine kinase).
- Elimination pathways: Hepatic metabolism and biliary excretion are the primary elimination pathways, with minimal renal clearance.
Dosage
Standard Dosage
Adults:
- 450 mg orally once daily with food.
- Continue treatment until disease progression or unacceptable toxicity.
Children:
- 500 mg/m² orally once daily with food.
- Safety and efficacy have not been fully established in pediatric patients. Treatment should be determined by a pediatric oncologist.
Special Cases:
- Elderly Patients (≥65 years): No dose adjustment is generally required.
- Patients with Renal Impairment: No dose adjustment is needed for mild to moderate renal impairment. Use with caution in severe renal impairment. No data available for patients on dialysis.
- Patients with Hepatic Dysfunction: For severe hepatic impairment (Child-Pugh C), reduce the dose by approximately one-third (rounded to the nearest multiple of 150 mg). No adjustment necessary for mild to moderate hepatic impairment (Child-Pugh A or B).
- Patients with Comorbid Conditions: Monitor patients with diabetes, cardiovascular disease, or electrolyte imbalances for potential exacerbation of their conditions.
Clinical Use Cases
Ceritinib is specifically indicated for ALK-positive NSCLC and is not typically used in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Refer to the Standard Dosage and Special Cases sections for detailed dosage adjustments based on age, organ dysfunction, and concomitant medications. Dose reductions may also be required for managing adverse reactions. See side effects section.
Side Effects
Common Side Effects
- Diarrhea
- Nausea
- Vomiting
- Fatigue
- Abdominal pain
- Decreased appetite
- Elevated liver enzymes (ALT, AST)
- Increased creatinine
- Rash
- Constipation
Rare but Serious Side Effects
- Hepatotoxicity
- Interstitial lung disease/pneumonitis
- QT interval prolongation
- Bradycardia
- Pancreatitis
- Hyperglycemia
Long-Term Effects
- Potential long-term effects from prolonged ceritinib use are not fully characterized but may include chronic liver dysfunction, cardiac complications, and secondary malignancies.
Adverse Drug Reactions (ADR)
- Clinically significant ADRs include severe hepatotoxicity, ILD/pneumonitis, QT prolongation, bradycardia, and pancreatitis. These necessitate immediate intervention and potential discontinuation of therapy.
Contraindications
- Hypersensitivity to ceritinib.
- Congenital long QT syndrome or persistent QTcF > 500 msec.
Drug Interactions
- Ceritinib is primarily metabolized by CYP3A4.
- CYP3A4 inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase ceritinib exposure.
- CYP3A4 inducers: Coadministration with strong CYP3A4 inducers may decrease ceritinib exposure.
- Drugs that prolong the QT interval: Avoid concomitant use.
- Drugs that cause bradycardia: Exercise caution.
- Grapefruit and grapefruit juice: Avoid consumption.
- Refer to drug interaction resources for a comprehensive list of potential drug interactions.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D
- Ceritinib may cause fetal harm.
- Effective contraception is required during treatment and for 6 months (females) or 3 months (males) after discontinuation.
- Breastfeeding: Ceritinib may be present in breast milk. Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: ALK tyrosine kinase inhibitor.
- Side Effects: Diarrhea, nausea, vomiting, fatigue, hepatotoxicity, ILD/pneumonitis, QT prolongation, bradycardia.
- Contraindications: Hypersensitivity, congenital long QT syndrome.
- Drug Interactions: CYP3A4 inhibitors/inducers, drugs prolonging QT interval.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended during breastfeeding.
- Dosage: 450 mg once daily with food (adults); 500 mg/m² once daily with food (children).
- Monitoring Parameters: Liver function tests (ALT, AST, bilirubin), QTc interval, blood glucose, lipase, amylase, complete blood count.
Popular Combinations
There are no established “popular combinations” for ceritinib. Typically, it is used as a single agent. Subsequent therapies after progression on ceritinib might include other ALK inhibitors or chemotherapy, based on individual patient factors and disease characteristics.
Precautions
- General Precautions: Monitor liver function, QTc interval, blood glucose, and complete blood count.
- Specific Populations: See Dosage section for specific recommendations regarding pregnant women, breastfeeding mothers, children, and the elderly.
- Lifestyle Considerations: Grapefruit and grapefruit juice should be avoided. Alcohol consumption should be limited.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ceritinib?
A: 450 mg orally once daily with food for adults. For children, it’s 500 mg/m² orally once daily with food. Dose modifications may be necessary for hepatic impairment and based on adverse reactions.
Q2: What are the most common side effects of Ceritinib?
A: Diarrhea, nausea, vomiting, fatigue, elevated liver enzymes, and increased creatinine are among the most common side effects.
Q3: How does Ceritinib work?
A: Ceritinib is an ALK tyrosine kinase inhibitor. It blocks ALK activity, which is involved in the growth and survival of cancer cells.
Q4: What are the serious side effects of Ceritinib?
A: Serious side effects can include hepatotoxicity, ILD/pneumonitis, QT prolongation, bradycardia, pancreatitis, and hyperglycemia.
Q5: What should patients avoid while taking Ceritinib?
A: Patients should avoid grapefruit and grapefruit juice, as they can increase Ceritinib levels. Concomitant use of certain medications should be avoided.
Q6: Can Ceritinib be used during pregnancy or breastfeeding?
A: Ceritinib is contraindicated during pregnancy due to potential harm to the fetus. Breastfeeding is also not recommended.
Q7: What are the monitoring parameters for Ceritinib?
A: Monitor liver function tests (ALT/AST/Bilirubin), QTc interval, blood glucose, lipase, amylase, and complete blood count regularly.
Q8: Is Ceritinib used in combination with other drugs?
A: Ceritinib is typically used as a single agent. It is not commonly used in combination with other medications for the treatment of ALK-positive NSCLC. Concomitant use of other medications requires a careful assessment due to potential drug interactions.
Q9: What should be done if a patient misses a dose of Ceritinib?
A: If a dose is missed and it is less than 12 hours until the next dose, skip the missed dose and return to the regular schedule. If more than 12 hours have passed, the missed dose should be taken as soon as possible, then resume the regular schedule.
