Alectinib

Introduction Overview

Generic Name

alectinib

Brand Name

Alecensa

Dosage Form

oral capsules

Drug Class

Multikinase inhibitors

Pharmacokinetics

Absorption

Alectinib exhibits adequate oral bioavailability, particularly when administered with food, which enhances its absorption. The drug is formulated as oral capsules, and clinical data indicate that taking Alecensa with meals increases systemic exposure, thus optimizing therapeutic drug levels. Absorption occurs primarily in the gastrointestinal tract, with peak plasma concentrations typically achieved within 4 to 6 hours post-dose. The presence of food plays a critical role in improving absorption, which is why clinical guidelines emphasize administration with meals to ensure consistent drug levels. Interindividual variability in absorption may occur due to gastrointestinal factors, but overall, alectinib demonstrates reliable oral absorption suited for outpatient therapy.

Distribution

Alectinib exhibits extensive tissue distribution following oral administration, supported by a high volume of distribution. It is highly protein bound (>99%), primarily to albumin, which influences the drug's pharmacokinetics and bioavailability. The drug is known to cross the blood-brain barrier effectively, a critical property that allows it to exert therapeutic effects on central nervous system (CNS) metastases common in ALK-positive non-small cell lung cancer (NSCLC) patients. Cerebrospinal fluid penetration is clinically significant, contributing to the control of CNS disease progression. Distribution is influenced by interactions with drug transporters, including P-glycoprotein substrates, which may modulate tissue uptake and clearance.

Metabolism

Metabolism of alectinib occurs predominantly in the liver via cytochrome P450 enzymes, mainly CYP3A4. The drug undergoes oxidative metabolism to form active metabolites, including M4, which retain pharmacologic activity against ALK rearrangements. The hepatic metabolism plays a key role in determining the duration of drug action and systemic exposure. Co-administration of CYP3A4 inducers or inhibitors can significantly alter plasma concentrations of alectinib and its metabolites, necessitating careful consideration of drug interactions. The involvement of multiple metabolic pathways also underscores the potential for variability in metabolism based on individual hepatic function and concomitant medications.

Elimination

The elimination of alectinib and its metabolites primarily occurs via the fecal route, with minimal renal excretion. Approximately 98% of the administered dose is recovered in feces, indicating biliary and hepatic clearance pathways are dominant. The half-life of alectinib is approximately 32.5 hours, supporting twice-daily dosing to maintain therapeutic plasma levels. Due to hepatic elimination, impaired liver function may significantly affect drug clearance and increase the risk of accumulation and toxicity. Renal impairment has a limited impact on elimination; however, monitoring is advised in severe cases. Regular liver function tests are recommended to detect hepatotoxicity early during therapy.

Dosage Forms

Adults

Alecensa is available as 150 mg oral capsules. The standard adult dosing regimen for ALK-positive non-small cell lung cancer involves taking four capsules (totaling 600 mg) orally twice daily, with food. Therapy is continued until disease progression or unacceptable toxicity occurs. Doses are to be swallowed whole and not crushed, chewed, or opened, to maintain drug integrity and absorption characteristics. Dose adjustments may be necessary in cases of toxicity or hepatic impairment as guided by clinical assessment and liver function testing.

Adolescents

The safety and efficacy of Alecensa in pediatric or adolescent populations have not been established, and the drug is currently approved for adult use only. No clinical dosing guidelines are available for adolescents; therefore, caution is warranted if off-label use is considered, and treatment should only be undertaken under specialist guidance with careful monitoring.

Special Populations

In patients with mild to moderate hepatic impairment, dose reduction or close monitoring is recommended due to increased drug exposure and potential hepatotoxicity. Alecensa is not recommended in severe hepatic impairment due to a lack of data. Renal impairment has limited influence on Alecensa pharmacokinetics, but severe renal dysfunction requires cautious use. There is insufficient data in pregnant or breastfeeding women, and Alecensa should be avoided due to potential teratogenic effects and unknown breast milk excretion. Geriatric patients may receive standard dosing, but individual monitoring for toxicity is advised due to possible comorbidities.

Mechanism Of Action

Alecensa (alectinib) functions as a potent and selective inhibitor of the anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase that is aberrantly activated in subsets of non-small cell lung cancer (NSCLC) due to gene rearrangements leading to oncogenic fusion proteins. By competitively binding to the ATP-binding site of ALK, alectinib blocks autophosphorylation and subsequent activation of downstream signaling pathways essential for malignant cell proliferation and survival, including the PI3K/AKT and RAS/MEK/ERK cascades. This targeted inhibition results in decreased tumor cell growth and induces apoptosis in ALK-positive cancer cells.

Unlike earlier generation ALK inhibitors, alectinib also targets the RET proto-oncogene kinase, expanding its antineoplastic activity. Its high selectivity for ALK and RET kinases reduces off-target effects commonly seen with less selective agents. Additionally, alectinib has demonstrated the capacity to penetrate the blood-brain barrier effectively, addressing central nervous system metastases by inhibiting ALK activity within the brain microenvironment.

Resistance to ALK inhibitors often emerges via secondary ALK mutations or activation of bypass signaling pathways; however, alectinib retains activity against many known resistance mutations, including L1196M, thereby offering clinical benefit in cases refractory to other ALK inhibitors. Ongoing research underscores its efficacy and tolerability profile compared to other tyrosine kinase inhibitors, making it a preferred agent for first-line and subsequent therapy in ALK-positive metastatic NSCLC.

Pharmacological Actions

Selective inhibition of anaplastic lymphoma kinase (ALK) enzyme activity
Targeted blockade of RET tyrosine kinase receptor
Inhibition of downstream oncogenic signaling pathways (PI3K/AKT, RAS/MEK/ERK)
Suppression of tumor cell proliferation and induction of apoptosis in ALK-positive cancer cells
Crossing the blood-brain barrier to treat central nervous system metastases
Activity against ALK mutations conferring resistance to earlier ALK inhibitors
Reduction of cancer cell viability by interrupting ALK-dependent survival signals
Minimal off-target kinase inhibition enhancing safety profile
Oral bioavailability facilitating outpatient treatment
Long half-life supporting twice-daily dosing regimen
Ability to reduce tumor burden in ALK-positive non-small cell lung cancer
Potential modulation of immune-related pathways indirectly
Synergistic effects when combined with other antineoplastic agents under investigation
Preventative efficacy as adjuvant therapy post-surgery in selected patients
Delay of disease progression and metastasis in treated populations

Therapeutic Clinical Uses

Treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) in adults
Adjuvant therapy to prevent recurrence after surgical resection of ALK-positive NSCLC tumors
Management of central nervous system metastases associated with ALK-positive NSCLC
Treatment of NSCLC patients harboring ALK gene rearrangements or mutations
Use in patients who have progressed on or are intolerant to other ALK inhibitors
Therapeutic option for RET-driven malignancies under clinical investigation
Targeted therapy for tumors dependent on ALK and RET kinase signaling
Treatment approach to improve progression-free survival in ALK-positive lung cancer
Use in combination protocols for advanced NSCLC to enhance outcomes
Management of lung cancer patients with confirmed ALK genetic markers
Supported as first-line treatment in ALK-positive NSCLC based on clinical trial data
Reduction of tumor burden and metastasis spread in NSCLC
Improvement of quality of life by oral administration and manageable side effects
Optimization of treatment in molecularly defined lung cancer subsets
Part of precision oncology treatment paradigms guided by genetic testing

Side Or Adverse Effects

Anemia, characterized by decreased red blood cell count or hemoglobin levels
Constipation, often mild to moderate in severity
Peripheral edema, including swelling of face, eyelids, hands, or lower legs
Fatigue or tiredness reported frequently during treatment
Muscle pain, myalgia, or muscular tenderness and weakness
Hepatotoxicity manifesting as liver enzyme elevations and potential liver injury
Dyspnea, cough, and other respiratory symptoms indicating possible lung toxicity
Bradycardia or slow heart rate, requiring monitoring and management
Gastrointestinal disturbances including nausea and vomiting
Rare hemolytic anemia due to premature breakdown of red blood cells
Potential hypersensitivity reactions such as rash or hives
Headache and dizziness in some patients during therapy
Increased risk of bleeding due to platelet function interference
Renal dysfunction or changes in urine color related to kidney injury
Photosensitivity leading to increased susceptibility to sunburn

Precautions

Regular monitoring of liver function tests at baseline and periodically during treatment
Close observation for signs of lung toxicity such as new or worsening respiratory symptoms
Assessment of heart rate and blood pressure before and during therapy to detect bradycardia
Avoidance of sunlight and use of sunscreen due to photosensitivity risk
Careful monitoring for muscle-related symptoms and creatine kinase levels to identify severe myopathy
Pregnancy prevention advised for both females and males due to teratogenic risk
Dose adjustments or temporary discontinuation may be needed upon detection of severe adverse effects
Patients should inform healthcare providers about all concomitant medications to avoid drug interactions
Close monitoring in patients with preexisting liver disease or hypertension
Cautious use in patients with renal impairment, although dose adjustment is not usually required
Avoid use in patients with known hypersensitivity to alectinib or formulation excipients
Educate patients about signs of allergic reactions and when to seek emergency care
Ensure adherence to dosing regimen with food to optimize drug absorption
Advise patients not to crush, chew, or open capsules to maintain efficacy
Observe for symptoms of anemia such as fatigue and pallor during treatment

Warnings

Risk of serious and potentially fatal hepatotoxicity requiring frequent liver function monitoring
Possibility of severe lung disease or interstitial lung disease (pneumonitis)
Risk of significant bradycardia and associated cardiac adverse events
Potential for severe muscle toxicity, including rhabdomyolysis, necessitating monitoring
Hemolytic anemia risk, which may require dose interruption or discontinuation
Allergic reactions including anaphylaxis can occur; immediate medical attention required
Not evaluated or recommended for use in pediatric populations due to safety concerns
Use during pregnancy associated with fetal harm and birth defects
Increased risk of toxicity if co-administered with strong CYP3A4 inhibitors or inducers
Potential for permanent discontinuation if severe adverse reactions occur
Possible tumor lysis syndrome during initiation of treatment
Photosensitivity reactions necessitate sun protection measures
Use caution in patients with pre-existing cardiac or lung diseases
Delay in dose administration advised if severe toxicity develops
Regular blood tests essential to detect early signs of adverse events

Contraindications

Known hypersensitivity to alectinib or any of its inactive ingredients
Pregnancy due to teratogenic potential and risk of fetal harm
Breastfeeding during treatment and for at least one week after last dose
Severe hepatic impairment or significant liver disease lacking safety data
Patients with a history of severe allergic reactions to this drug
Concurrent use of strong CYP3A4 inducers or inhibitors without medical supervision
Use in pediatric patients, as safety and efficacy have not been established
Uncontrolled cardiovascular conditions such as severe bradycardia or arrhythmias
Prior severe drug-induced liver injury from alectinib treatment
Patients unable to swallow capsules whole or with significant gastrointestinal malabsorption
Known hypersensitivity to any multikinase inhibitors with similar formulation
Use in patients with unresolved severe lung disease other than NSCLC
Combination with agents contraindicated due to overlapping toxicities
Patients with active infections or immunocompromised status without close monitoring
Known sensitivity to formulation excipients such as lactose or capsule shell components

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may increase alectinib plasma concentrations
Strong CYP3A4 inducers (e.g., rifampin, carbamazepine) may decrease alectinib effectiveness
Concomitant use with other drugs causing bradycardia may exacerbate heart rate slowing
Potential interaction with acid-reducing agents affecting absorption not significant but monitor clinically
Avoid combination with other hepatotoxic agents to reduce liver injury risk
Drugs that affect P-glycoprotein transporter may alter alectinib distribution and clearance
Co-administration with anticoagulants warrants monitoring for bleeding risk
Herbal supplements such as St. John's Wort may reduce alectinib plasma levels through CYP3A4 induction
Caution when used with other antineoplastic agents due to overlapping toxicities
Concomitant use with immunosuppressants may require dose adjustments
No significant interaction observed with vitamins or common over-the-counter medications
Drug interactions may necessitate dose adjustment or enhanced clinical monitoring
Patients should inform healthcare providers of all medications including supplements
Potential interactions with cardiac drugs like beta-blockers due to additive bradycardia effects
Careful consideration required when switching from or to other ALK inhibitors to avoid drug-drug interactions

Preparations Of The Drug

Alecensa 150 mg oral capsules
Capsules contain active ingredient alectinib hydrochloride
Inactive ingredients include lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, carboxymethylcellulose calcium
Capsule shell composed of hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax
Printing inks used for capsule markings include red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate
Available in blister packs or bottles as per manufacturer specifications
Intended for oral administration with food
No liquid or injectable formulations commercially available
Packaged for room temperature storage avoiding moisture and light
Manufactured and distributed by Genentech, Inc.