Usage
- Alectinib is prescribed for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). It is used for patients with metastatic NSCLC and also as adjuvant therapy after surgical resection of a tumor in patients with ALK-positive NSCLC.
- Pharmacological Classification: Alectinib is a kinase inhibitor, specifically an ALK and RET (Rearranged during Transfection) tyrosine kinase inhibitor.
- Mechanism of Action: Alectinib works by selectively inhibiting the activity of ALK tyrosine kinase. This kinase is often overactive in certain types of cancer, including ALK-positive NSCLC. By blocking ALK, alectinib helps to slow or stop the growth and spread of cancer cells. It has also shown activity against mutant forms of the ALK enzyme, including those resistant to crizotinib.
Alternate Names
- International Nonproprietary Name (INN): alectinib
- Brand Name: Alecensa
How It Works
- Pharmacodynamics: Alectinib inhibits ALK phosphorylation and its downstream signaling pathways (STAT3 and PI3K/AKT), ultimately leading to cancer cell death (apoptosis). It is highly selective for ALK and RET and demonstrates activity against various ALK mutations, including those conferring resistance to crizotinib.
- Pharmacokinetics:
- Absorption: Rapidly absorbed following oral administration. Bioavailability is enhanced when taken with food (around 37% under fed conditions).
- Metabolism: Primarily metabolized by CYP3A4, with its active metabolite (M4) having comparable potency.
- Elimination: Primarily eliminated via hepatic metabolism and biliary excretion. Renal elimination is negligible. Alectinib has a half-life of approximately 33 hours.
- Mode of Action: Alectinib competitively binds to the ATP-binding site of ALK tyrosine kinase, thereby inhibiting its catalytic activity. This prevents the phosphorylation of downstream signaling proteins, which are essential for cancer cell growth, proliferation, and survival.
- Receptor binding/Enzyme inhibition/Neurotransmitter modulation: Alectinib primarily acts through enzyme inhibition (ALK tyrosine kinase).
Dosage
Standard Dosage
Adults:
- 600 mg orally twice daily with food. Treatment continues until disease progression or unacceptable toxicity.
Children:
- The safety and efficacy of alectinib in children and adolescents below 18 years have not been fully established. Some studies have investigated its use with adjusted dosages in pediatric patients with ALK-positive anaplastic large cell lymphoma (ALCL).
Special Cases:
- Elderly Patients: No dose adjustment is required, although closer monitoring for adverse effects is recommended.
- Patients with Renal Impairment: No dose adjustment needed.
- Patients with Hepatic Dysfunction:
- Mild to moderate impairment: No adjustment needed.
- Severe impairment (Child-Pugh C): 450 mg orally twice daily.
- Patients with Comorbid Conditions: Dosage adjustments may be necessary based on specific comorbidities.
Clinical Use Cases
Alectinib’s primary use is systemic therapy for ALK-positive NSCLC and as an adjuvant therapy after surgery for those with ALK+ NSCLC. It is not typically employed in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency scenarios.
Dosage Adjustments
- Dose reductions, interruptions, or discontinuation may be required based on adverse reactions, including hepatotoxicity, ILD/pneumonitis, myalgia with CPK elevation, bradycardia, and hematologic toxicities.
Side Effects
Common Side Effects:
- Constipation, myalgia, fatigue, edema, rash, cough, nausea, diarrhea, vomiting, stomatitis, dysgeusia, headache, increased weight, elevated alkaline phosphatase or serum creatinine, back pain, anemia, lymphopenia, vision disorders, acute kidney injury.
Rare but Serious Side Effects:
- Hepatotoxicity (liver damage), interstitial lung disease (ILD)/pneumonitis, severe myalgia with elevated creatine phosphokinase (CPK), hemolytic anemia, bradycardia, gastrointestinal perforation.
Long-Term Effects:
- Long-term effects are still being studied, but potential complications could include chronic liver disease or pulmonary fibrosis.
Adverse Drug Reactions (ADR):
- As mentioned above, serious ADRs include hepatotoxicity, ILD/pneumonitis, severe myalgia, hemolytic anemia, bradycardia, and gastrointestinal perforation.
Contraindications
- Hypersensitivity to alectinib or any of its components.
Drug Interactions
- CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors (e.g., posaconazole, itraconazole, ketoconazole, voriconazole, clarithromycin, ritonavir) may increase alectinib concentrations and requires dose adjustments or close monitoring.
- CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, St. John’s wort) can decrease alectinib concentrations, potentially reducing efficacy.
- Other clinically significant interactions can occur with various medications, including certain antibiotics, antifungals, antivirals, anticonvulsants, and other cancer therapies.
- Food and lifestyle factors like grapefruit juice can also influence alectinib’s metabolism.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Alectinib is contraindicated during pregnancy. It can cause fetal harm based on animal studies and its mechanism of action. Effective contraception is mandatory during treatment and for a period after the last dose (3 months for men, 1 week for women).
- Breastfeeding: Alectinib is not recommended during breastfeeding due to potential risks to the infant. Breastfeeding should be discontinued during treatment and for 1 week after the last dose.
Drug Profile Summary
- Mechanism of Action: ALK tyrosine kinase inhibitor.
- Side Effects: Common: Constipation, myalgia, fatigue. Serious: Hepatotoxicity, ILD/pneumonitis.
- Contraindications: Hypersensitivity to alectinib, pregnancy.
- Drug Interactions: CYP3A4 inhibitors and inducers, multiple other drugs.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: 600 mg twice daily with food; adjustments needed for severe hepatic impairment.
- Monitoring Parameters: Liver function tests, CPK, pulmonary function, heart rate, blood pressure, complete blood counts.
Popular Combinations
- Alectinib is typically used as a single agent. Combining it with other targeted therapies or chemotherapy may be explored in the future or in clinical trials.
Precautions
- Monitor for hepatotoxicity, ILD/pneumonitis, myalgia/CPK elevation, bradycardia, and other potential side effects.
- Avoid strong CYP3A4 inhibitors and inducers.
- Contraception is essential during treatment and for a period afterwards.
- Patients should avoid sun exposure and use appropriate sun protection.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Alectinib?
A: The standard dose is 600 mg orally twice daily with food for adults. Patients with severe hepatic impairment should receive 450 mg twice daily.
Q2: What are the most common side effects of Alectinib?
A: Constipation, myalgia (muscle pain), fatigue, edema (swelling), and rash are common side effects.
Q3: How does Alectinib work?
A: It inhibits ALK tyrosine kinase, blocking signals that promote cancer cell growth and survival.
Q4: Who should not take Alectinib?
A: Patients with hypersensitivity to alectinib and pregnant women should not take this medication.
Q5: What are the serious side effects of Alectinib?
A: Liver problems (hepatotoxicity), lung inflammation (ILD/pneumonitis), severe muscle pain, hemolytic anemia, slow heart rate (bradycardia) and gastrointestinal perforation are rare but serious side effects.
Q6: Does Alectinib interact with other medications?
A: Yes, it interacts with numerous drugs, especially those affecting CYP3A4 enzyme activity (like certain antibiotics, antifungals and antivirals).
Q7: Can I take Alectinib if I have kidney problems?
A: Yes, typically no dose adjustments are needed for mild to moderate renal impairment.
Q8: Can Alectinib be used during pregnancy or breastfeeding?
A: No, it’s contraindicated in pregnancy and not recommended during breastfeeding.
Q9: What should patients be monitored for during Alectinib treatment?
A: Regular monitoring of liver function, CPK levels, pulmonary function, heart rate and blood pressure, and complete blood counts are essential.
