Brigatinib

Introduction Overview

Generic Name

brigatinib

Brand Name

Alunbrig

Dosage Form

oral tablets

Drug Class

multikinase inhibitors (ALK inhibitor)

Pharmacokinetics

Absorption

Brigatinib is administered orally and exhibits good bioavailability with absorption occurring primarily in the gastrointestinal tract. Food intake does not significantly affect the rate or extent of absorption, permitting dosing with or without food. Peak plasma concentrations (Cmax) are achieved approximately 1 to 4 hours post-dose. The absorption profile supports once-daily dosing to maintain effective plasma levels. Variability in absorption between patients is moderate and not significantly influenced by demographic factors such as age or sex.

Distribution

Brigatinib demonstrates extensive tissue distribution with a large volume of distribution, reflecting extensive penetration into tissues, including the lungs and potentially the central nervous system. Plasma protein binding is approximately 91%, primarily to albumin and alpha-1 acid glycoprotein, which may influence drug interactions and free drug concentration. The drug's ability to reach tumor sites such as metastatic lesions is clinically significant for its anti-cancer effects in ALK-positive non-small cell lung cancer (NSCLC).

Metabolism

Brigatinib is extensively metabolized in the liver, predominantly by the cytochrome P450 enzymes CYP2C8 and CYP3A4. Its metabolites are pharmacologically inactive. The metabolism involves oxidative pathways including N-demethylation and hydroxylation. Due to its CYP3A4-mediated metabolism, co-administration with strong CYP3A4 inhibitors or inducers can significantly alter brigatinib plasma levels, necessitating dosage adjustment. Hepatic impairment may affect metabolism and clearance, warranting clinical monitoring.

Elimination

Elimination of brigatinib occurs mainly via the feces (~65%) and urine (~25%), primarily as metabolites. The elimination half-life is approximately 25 hours, supporting once-daily dosing. Steady-state plasma concentrations are achieved within 15 days of consistent dosing. Renal elimination of unchanged drug is minimal, thus moderate renal impairment may have limited effect on clearance, but severe impairment or dialysis effects are not extensively studied. Hepatic impairment may reduce clearance, emphasizing need for caution and clinical monitoring.

Dosage Forms

Adults

Alunbrig is supplied as oral tablets for adult patients, primarily used in treating ALK-positive metastatic non-small cell lung cancer (NSCLC). The standard dosing regimen starts with 90 mg orally once daily for the first 7 days (initial dose). If this dose is well tolerated, the maintenance dose is increased to 180 mg orally once daily. Therapy continues until disease progression or unacceptable toxicity occurs. The tablets should be swallowed whole and may be taken with or without food. If a dose is missed, it should be skipped with the next dose taken at the regular time. No doubling of doses is recommended.

Adolescents

Currently, brigatinib (Alunbrig) is not approved for use in pediatric or adolescent populations. Use in these groups should be under strict clinical trial protocols or on an individual compassionate basis, with dosing guided by clinical pharmacology and safety data, which remain limited.

Special Populations

In special populations such as patients with hepatic or renal impairment, dose adjustments may be necessary due to altered metabolism and elimination. Patients with severe liver disease need clinical monitoring, though specific dosage modifications are not well established. Renal impairment has limited effect on elimination of brigatinib, but caution is advised in severe cases. Pregnant women should avoid use due to teratogenic risks. Lactating women should not breastfeed during treatment and for at least one week after the last dose. Elderly patients do not require special dosing but should be monitored for side effects.

Mechanism Of Action

Brigatinib, marketed as Alunbrig, is a potent oral tyrosine kinase inhibitor targeting the anaplastic lymphoma kinase (ALK) enzyme and other kinases. ALK is involved in cellular signaling pathways that regulate cell growth and survival. In non-small cell lung cancer (NSCLC), genetic alterations, like the EML4-ALK fusion gene, result in constitutively active ALK kinase promoting uncontrolled cell proliferation. Brigatinib binds competitively to the ATP-binding site of the ALK kinase domain, inhibiting its autophosphorylation and downstream signaling, thereby interrupting multiple oncogenic signaling pathways including PI3K/AKT, RAS/MAPK, and JAK/STAT.

Pharmacological Actions

Potent inhibition of ALK tyrosine kinase activity
Inhibition of ROS1 and mutant forms of ALK resistant to first-generation ALK inhibitors
Blockade of downstream cellular signaling leading to cell cycle arrest and apoptosis
Reduction in cancer cell proliferation and tumor progression
Partial inhibition of other kinases such as IGF-1R, FLT3, EGFR, contributing to anti-tumor effects

Therapeutic Clinical Uses

Treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC)
Indicated for patients who have progressed on or are intolerant to crizotinib
Used specifically for tumors harboring ALK gene rearrangements
Provides therapy option in advanced metastatic NSCLC with brain metastases
Treatment aimed to delay disease progression and improve survival in ALK-positive NSCLC patients

Side Or Adverse Effects

Pulmonary toxicity including interstitial lung disease and pneumonitis
Vision disorders such as blurred vision, double vision, photophobia, and visual floaters
Hypertension (high blood pressure)
Hyperglycemia (high blood sugar) with symptoms like increased thirst and urination
Bradycardia (slow heart rate), potentially causing syncope
Muscle pain and weakness, unexplained by other causes
Pancreatitis presenting as upper abdominal pain radiating to the back
Gastrointestinal effects: nausea, vomiting, diarrhea
Cough and dyspnea (difficulty breathing)
Skin rash and pruritus
Fatigue and headache
Rare allergic reactions including anaphylaxis

Precautions

Conduct ALK gene testing prior to initiating therapy to confirm indication
Monitor for pulmonary symptoms closely after initiation to detect early lung toxicity
Regular blood pressure monitoring due to risk of hypertension
Frequent blood glucose monitoring in diabetic or predisposed patients
Assess cardiac function and heart rate during treatment, especially in patients with cardiovascular history
Advise patients on use of effective non-hormonal contraception to prevent pregnancy
Avoid grapefruit and grapefruit juice due to interaction potential
Evaluate liver and kidney function before and during treatment
Do not breastfeed during therapy and for at least one week after cessation
Discontinue treatment promptly upon severe adverse effects

Warnings

Severe pulmonary adverse events including fatal interstitial lung disease
Vision abnormalities requiring ophthalmologic evaluation
Risk of hypertensive crises if uncontrolled
Severe hyperglycemia leading to diabetic ketoacidosis
Bradyarrhythmias causing syncope or presyncope
Pancreatitis with abdominal pain and elevated pancreatic enzymes
Potential teratogenicity and fetal harm; pregnancy avoidance mandatory
Hypersensitivity reactions including anaphylaxis
Possible delay or discontinuation of cancer therapy due to adverse events

Contraindications

Known hypersensitivity to brigatinib or any component of Alunbrig tablets
Pregnancy due to potential fetal harm
Patients unable to comply with contraception requirements during therapy
Severe uncontrolled cardiac conditions may contraindicate use

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may increase brigatinib plasma levels and toxicity
CYP3A4 inducers (e.g., rifampin, carbamazepine) reduce brigatinib effectiveness by lowering plasma levels
Grapefruit products can elevate brigatinib concentrations and are contraindicated
Concomitant use with drugs that prolong QT interval may increase risk of arrhythmias
Interactions with other multikinase inhibitors may increase adverse effects
Potential interaction with hormonal contraceptives reducing their efficacy
Caution with antidiabetic drugs due to hyperglycemia risk
Interaction with P-glycoprotein substrates may alter brigatinib pharmacokinetics

Preparations Of The Drug

Oral tablets: 90 mg strength
Oral tablets: 180 mg strength
Tablets intended for once-daily oral administration
Available as film-coated tablets
Packaging typically in blister cards or bottles as per manufacturer