Alectinib is an oral, targeted anticancer drug and a second-generation anaplastic lymphoma kinase (ALK) inhibitor, primarily used to treat non-small cell lung cancer (NSCLC) with ALK gene rearrangements. It works by selectively blocking ALK signaling pathways, which are responsible for cancer cell growth and survival, and is particularly effective against brain metastases due to its ability to penetrate the central nervous system. The development of alectinib followed the discovery of ALK rearrangements in NSCLC in the early 2000s, which led to the first-generation ALK inhibitor, crizotinib. While crizotinib showed initial efficacy, it was limited by acquired resistance and poor brain penetration. Alectinib was developed to overcome these limitations and was first approved in Japan in 2014, followed by approvals in the US and Europe. Clinical trials have shown that alectinib provides longer progression-free survival, better central nervous system activity, and improved overall outcomes, making it a preferred treatment option for patients with ALK-positive NSCLC.
BRAND NAMES
The primary brand name for alectinib, a targeted cancer drug, is Alecensa (ALECENSA), used for treating ALK-positive non-small cell lung cancer (NSCLC) and other cancers.
Other, less common or regional names/variations include Alecensaro, Alecinix, and Alnib, but Alecensa is the globally recognized brand.
MECHANISM OF ACTION
Alectinib works by selectively and potently inhibiting the Anaplastic Lymphoma Kinase (ALK) tyrosine kinase, a protein that is often abnormally activated in cancers such as ALK-positive non-small cell lung cancer through fusion proteins or mutations. By directly binding to ALK, alectinib prevents its phosphorylation, disrupting downstream signaling pathways, including STAT3 and AKT, which are responsible for promoting cell growth and survival. This inhibition ultimately reduces tumor cell proliferation and induces apoptosis, leading to cancer cell death.
PHARMACOKINETICS
Absorption
Alectinib is orally administered and is absorbed relatively slowly, reaching peak plasma concentrations approximately 4–6 hours after dosing. Its absorption is enhanced when taken with food, which increases bioavailability. The drug exhibits moderate oral bioavailability, and consistent dosing with meals is recommended to ensure optimal therapeutic levels.
Distribution
Alectinib has a relatively large volume of distribution, approximately 3.3 L/kg, indicating extensive distribution into tissues, including the lungs and central nervous system.
Metabolism
Alectinib is mainly metabolized in the liver by the CYP3A4 enzyme into its primary active metabolite, M4. The drug is predominantly excreted in the feces (about 98%). Its metabolism is generally not markedly affected by strong CYP3A inhibitors or inducers, and alectinib itself has minimal impact on other CYP3A substrates, often reducing the need for dose adjustments in drug interactions. However, hepatic impairment can alter drug exposure and may require careful monitoring.
Excretion
Alectinib is primarily excreted through the feces (around 98%), mainly as unchanged drug, with minimal amounts (<1%) eliminated via urine.
PHARMACODYNAMICS
Alectinib is a second-generation, highly selective oral tyrosine kinase inhibitor (TKI) that exerts its pharmacodynamic effect mainly by inhibiting the activity of the anaplastic lymphoma kinase (ALK) fusion protein in cancer cells.
ADMINISTRATION
Alectinib is administered orally, usually at a dose of 600 mg twice daily with food to enhance absorption. It should be taken at the same times each day to maintain consistent blood levels. Dose adjustments may be necessary in patients with hepatic impairment or when used with certain interacting drugs. Regular medical monitoring is recommended to assess effectiveness and manage potential side effects.
DOSAGE AND STRENGTH
Recommended dose: 600 mg orally twice daily with food.
Capsule/tablet strengths: Commonly available as 150 mg or 250 mg capsules.
Adjustment: Dose modification may be required in cases of hepatic impairment or drug interactions, as guided by a physician.
Administration: Consistent timing with meals is important for optimal absorption.
DRUG INTERACTIONS
Alectinib has a relatively low potential for drug interactions compared to many other tyrosine kinase inhibitors, but caution is still necessary. Its metabolism primarily involves CYP3A4, so co-administration with strong CYP3A inhibitors, such as ketoconazole or clarithromycin, may increase plasma levels, while strong CYP3A inducers, like rifampin or carbamazepine, can reduce its effectiveness. Alectinib has minimal impact on other CYP3A substrates, so dose adjustments of concurrent medications are usually not required. It should be taken consistently with meals to ensure adequate absorption, and while antacids or proton pump inhibitors do not significantly affect its activity, maintaining consistent administration is recommended.
FOOD INTERACTIONS
Alectinib should be taken with food to enhance absorption, but the type of meal is important. Consuming it with a high-fat meal can increase drug levels by approximately threefold, whereas taking it with low-fat foods, such as yogurt, may significantly reduce absorption and risk subtherapeutic levels or treatment failure. Patients are advised to take a moderate to substantial meal like a regular breakfast or lunch to ensure optimal efficacy, and to avoid low-fat options for the dose.
CONTRAINDICATIONS
Alectinib is contraindicated in patients with a known hypersensitivity to alectinib or any of its excipients. It should also be avoided in individuals with severe hepatic impairment, as impaired liver function can lead to significantly increased drug exposure and toxicity. Use during pregnancy is generally not recommended due to potential harm to the fetus. Caution is advised in patients with pre-existing interstitial lung disease or severe cardiac conditions, as alectinib may exacerbate these issues.
SIDE EFFECTS
Fatigue.
Constipation
Edema.
Muscle pain, aches, or stiffness
Anemia.
Weight gain
Back pain
Nausea, vomiting, or diarrhea
Increased sensitivity to sunlight
OVERDOSE
There is limited clinical experience with alectinib overdose. In the event of overdose, no specific antidote is available, and management is primarily supportive and symptomatic. Patients should be closely monitored for exaggerated adverse effects such as liver toxicity, bradycardia, muscle pain or elevated creatine phosphokinase, gastrointestinal disturbances, and fatigue. Treatment may include discontinuation of alectinib, supportive care, and appropriate medical monitoring until symptoms resolve.
TOXICITY
Alectinib toxicity can range from common, usually manageable side effects such as fatigue, muscle pain (myalgia), edema, and constipation to more serious complications, including liver injury (hepatotoxicity), lung problems, kidney dysfunction (nephrotoxicity), and bradycardia (slow heart rate). Management typically involves dose reduction or temporary discontinuation, along with careful monitoring of liver and kidney function and heart rate.
