alectinib

Action and Spectrum

Actions and Spectrum: 

alectinib is a medication used to treat certain non-small cell lung cancer types. Class of drugs to which it belongs is tyrosine kinase inhibitors (TKIs) which works by blocking the activity of anaplastic lymphoma kinase and other receptors involved in the growth and survival of cancer cells. 

The spectrum of activity of alectinib includes the treatment of ALK-positive non-small cell lung cancer, which means it is effective against cancer cells with a specific genetic mutation called ALK rearrangement. alectinib may also be effective against other types of cancer cells that have mutations in related genes, such as ROS1. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Myalgia (23-29%) 

Increased weight (11%) 

Anemia (56%) 

Constipation (34%) 

Hyperglycemia (36%) 

Hypokalemia (29%) 

Increased alkaline phosphatase (47%) 

Lymphopenia (22%) 

Increased CPK (43%) 

Rash (15-18%) 

Bradycardia (11%) 

Hypophosphatemia (21%) 

Cough (19%) 

Hypocalcemia (32%) 

Dyspnea (16%) 

Increased AST (51%) 

Nausea (14-18%) 

Edema (22-30%) 

Vomiting (7-12%) 

Hyperbilirubinemia (39%) 

Headache (17%) 

Back pain (12%) 

Diarrhea (12-16%) 

Hyponatremia (20%) 

Increased ALT (34%) 

Increased creatinine (28%) 

Fatigue (26-41%) 

1-10% 

Increased CPK (4.6%) 

Dyspnea (3.6%) 

Hypophosphatemia (2.8%) 

Lymphopenia (4.6%) 

Hyperbilirubinemia (2.4%) 

Myalgia (1.2%) 

Vision disorders (4.6%) 

Anemia (2%) 

Dysgeusia (3.3%) 

Increased AST (3.6%) 

Hypokalemia (4%) 

Increased ALT (4.8%) 

Increased alkaline phosphatase (1.2%) 

Fatigue (1.2%) 

Hyponatremia (2%) 

Diarrhea (1.2%) 

Renal impairment (3.9%) 

Hyperglycemia (2%) 

<1% 

Vomiting (0.4%) 

Edema (0.7-0.8%) 

Dysgeusia (0.7%) 

Increased weight (0.4%) 

Headache (0.8%) 

Hypocalcemia (0.4%) 

Nausea (0.7%) 

Rash (0.4-0.7%) 

Black Box Warning

Black Box Warning: 

The black box warning for alectinib states that it may cause severe or life-threatening inflammation of the lungs, called pneumonitis. Symptoms of pneumonitis may include difficulty breathing, cough, and fever. If pneumonitis is suspected, alectinib should be discontinued and appropriate treatment initiated. 

Other warnings and precautions associated with alectinib include the risk of hepatotoxicity (liver toxicity), bradycardia (slow heart rate), and central nervous system (CNS) effects such as dizziness and confusion. alectinib may also interact with other medications, including certain antibiotics, antifungals, and grapefruit or grapefruit juice, which can enhance the risk of side effects or diminish the effectiveness of alectinib. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: alectinib is contraindicated in patients with a known hypersensitivity to the drug components. 
• Strong CYP3A inhibitors: alectinib is metabolized by the liver enzyme CYP3A. The concomitant use of potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, and grapefruit juice, can increase alectinib exposure and the risk of toxicity. 
• Strong CYP3A inducers: Strong CYP3A inducers, such as rifampin, phenytoin, and carbamazepine, can decrease alectinib exposure and the effectiveness of the medication. 
• Bradycardia: alectinib can cause bradycardia, which is a slow heart rate. Patients with preexisting bradycardia, conduction system abnormalities, or cardiac disease should use it with caution. 
• Pregnancy and breastfeeding: alectinib can cause fetal harm when administered to a pregnant woman. It is also unknown whether alectinib is excreted in human milk.  

Caution 

• Hepatic impairment: alectinib is metabolized in the liver, and patients with hepatic impairment may have an increased risk of toxicity. alectinib should be used cautiously in patients with moderate or severe hepatic impairment. 
• Renal impairment: alectinib has not been researched in patients with severe or end-stage renal disease. Dose adjustments may be necessary for patients with mild to moderate renal impairment. 
• CNS effects: alectinib can cause CNS effects, such as dizziness and confusion. Patients should be advised to avoid driving or operating machinery until they know how the medication affects them. 
• Interstitial lung disease: alectinib can cause interstitial lung disease (ILD), a severe and potentially fatal side effect.  
• QT prolongation: alectinib can cause QT prolongation, which is a rare but potentially life-threatening arrhythmia.  
• Immunocompromised patients: alectinib may increase the risk of opportunistic infections in immunocompromised patients. 
• Gastrointestinal toxicity: alectinib can cause gastrointestinal toxicity, such as nausea, vomiting, and diarrhea. Patients should be advised to report any severe or persistent gastrointestinal symptoms to their healthcare provider. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned 

Lactation:   

Excreted into human milk is Not known. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies do not show risk to the fetus in the first/later trimester.        
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women        
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.       
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.        
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.        
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology:

alectinib is a small tyrosine kinase inhibitor that selectively targets the anaplastic lymphoma kinase (ALK) protein. The ALK protein is produced by the fusion of two genes, resulting in an abnormal protein that drives the growth of cancer cells in some types of non-small cell lung cancer (NSCLC). 

alectinib works by binding to the ATP-binding site of the ALK protein, thereby inhibiting its activity and blocking the downstream signaling pathways that promote cancer cell growth and survival. 

Pharmacodynamics: 

Mechanism of action: alectinib is a tyrosine kinase inhibitor that targets ALK and RET. It inhibits ALK phosphorylation and its downstream signaling proteins STAT3 and AKT. According to nonclinical studies, this results in decreased tumor cell viability in various cell lines that carry ALK fusions, amplifications, or activating mutations. The primary active metabolite of alectinib, M4, has comparable in vitro potency and activity. Both alectinib and M4 have exhibited in vitro and in vivo effectiveness against various mutant forms of the ALK enzyme, including specific mutations found in NSCLC tumors of patients who have failed to respond to crizotinib treatment. 

Pharmacokinetics: 

Absorption 

When taken with food, the absolute bioavailability of the drug is 37%. The peak plasma time is approximately 4 hours after administration with food. At steady-state, the peak plasma concentration is 665 ng/mL for the drug and 246 ng/mL for the primary active metabolite, M4. The area under the curve (AUC) is 7430 ng·h/mL for the drug and 2810 ng·h/mL for M4. A Steady-state is reached after seven days of administration. 

Distribution 

Both the parent drug and its major active metabolite, M4, are highly protein bound (>99%). The volume of distribution (Vd) is 4016 L for the drug and 10,093 L for M4. 

Metabolism 

CYP3A4 primarily metabolizes alectinib into its major active metabolite, M4. Subsequently, M4 is also metabolized by CYP3A4. Additionally, M4 is a substrate of P-glycoprotein (P-gp). 

Elimination and Excretion 

The half-life of the parent drug is approximately 33 hours, while the half-life of the primary active metabolite M4 is around 31 hours. The clearance of the drug is 81.9 L/hr, while the clearance of M4 is 217 L/hr. alectinib and M4 are primarily eliminated via feces, with 84% of the drug and 6% of M4 excreted through feces. Less than 0.5% of the drug is excreted in the urine. 

Adminstartion

Administration: 

Oral administration 

alectinib is available in capsule form and is taken orally. The capsules should be consumed whole with water and taken with or without food. It is essential to take the medication simultaneously each day to maintain a consistent level of the drug in the body. 

If a dose is missed, it is recommended to take it as soon as possible. However, if the next scheduled dose is missed, it should be skipped, and the following dose should be taken at the appropriate time. It is important to avoid taking a double dose of the medication to compensate for the missed dose.

alectinib should be stored at room temperature, away from light and moisture. It should also be kept out of reach of children. Patients should not crush, chew, or open the capsules, as this can result in decreased effectiveness and an increased risk of adverse effects. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: alectinib 

Pronounced: uh-LEK-tih-nib 

Why do we use alectinib? 

alectinib is a medication used to treat certain types of non-small cell lung cancer (NSCLC). Specifically, it is indicated for treating patients with metastatic NSCLC whose tumors have an anaplastic lymphoma kinase (ALK) fusion gene, as detected by an FDA-approved test. 

alectinib is used as a first-line treatment for ALK-positive metastatic NSCLC and for patients who have previously been treated with crizotinib, another ALK inhibitor, but have progressed on that treatment. 

alectinib works by blocking the activity of the abnormal ALK protein, which is produced by the ALK fusion gene and drives the growth of cancer cells in some types of NSCLC. 

It is essential for patients to discuss the potential benefits and risks of alectinib with their healthcare provider and to report any new or worsening symptoms immediately.