Brigatinib

Uses

Brigatinib is used for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.
Pediatric Use: The safety and effectiveness of Brigatinib in pediatric patients have not been established.

Geriatric Use: Of the 359 patients enrolled in the ALTA 1L Brigatinib arm and in ALTA, 26.7% were 65 and older
and 7.5% were 75 and older. No overall differences in safety or effectiveness were observed between patients ≥65 years and younger patients.

Hepatic Impairment: No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) or
moderate hepatic impairment (Child-Pugh B). Reduce the dose of Brigatinib for patients with severe hepatic impairment (Child-Pugh C)

Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment ClCr 30 to 89 mL/min by Cockcroft-Gault. Reduce the dose of Brigatinib for patients with severe renal impairment (ClCr 15 to 29 mL/min)

Brigatinib is also used to associated treatment for these conditions: Metastatic Non-Small Cell Lung Cancer

How Brigatinib works

Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins.

Dosage

Brigatinib dosage

The recommended dosage for Brigatinib is 90 mg orally once daily for the first 7 days; then increase the dose to 180 mg orally once daily. Administer Brigatinib until disease progression or unacceptable toxicity. If Brigatinib is interrupted for 14 days or longer for reasons other than adverse reactions, resume treatment at 90 mg once daily for 7 days before increasing to the previously tolerated dose. Brigatinib may be taken with or without food. Instruct patients to swallow tablets whole. Do not crush or chew tablets.

Side Effects

The most common adverse reactions (≥25%) with Brigatinib were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, and dyspnea.

Toxicity

Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis.

Precaution

• Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold Brigatinib for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue Brigatinib.
• Hypertension: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold Brigatinib, then dose reduce or permanently discontinue.
• Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold Brigatinib, then dose reduce or permanently discontinue.
• Visual Disturbance: Advise patients to report visual symptoms. Withhold Brigatinib and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue Brigatinib.
• Creatine Phosphokinase (CPK) Elevation: Monitor CPK levels regularly during treatment. Based on the severity and with muscle pain or weakness, withhold Brigatinib, then resume or reduce dose.
• Pancreatic Enzymes Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold Brigatinib, then resume or reduce dose.
• Hyperglycemia: Assess fasting serum glucose prior to starting Brigatinib and regularly during treatment. If not adequately controlled with optimal medical management, withhold Brigatinib, then consider dose reduction or permanently discontinue, based on severity.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use a non-hormonal method of effective contraception.

Interaction

• CYP3A Inhibitors: Avoid coadministration of Brigatinib with strong or moderate CYP3A inhibitors. If coadministration of a strong or moderate CYP3A inhibitor is unavoidable, reduce the dose of Brigatinib.
• CYP3A Inducers: Avoid coadministration of Brigatinib with strong or moderate CYP3A inducers. If coadministration of a moderate CYP3A inducer is unavoidable, increase the dose of Brigatinib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of brigatinib.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of brigatinib and may reduce its serum concentration.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of brigatinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Itraconazole, a potent CYP450 3A4 inhibitor, has been shown to double brigatinib systemic exposure (AUC) in healthy volunteers.

Increased exposure to brigatinib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, hypertension, bradycardia, hyperglycemia, visual disturbances, lymphopenia, anemia, and elevations in pancreatic enzymes and creatine phosphokinase.

Food does not significantly affect the oral bioavailability of brigatinib.

When brigatinib was administered to healthy volunteers after a high-fat meal (920 calories; 59 g fat, 58 g carbohydrates, 40 g proteins), brigatinib peak plasma concentration (Cmax) decreased by 13% and systemic exposure (AUC) did not change compared to administration after overnight fasting.

MANAGEMENT: Brigatinib may be taken with or without food.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with brigatinib.

Brigatinib Drug Interaction

Major: diltiazemModerate: lithiumUnknown: charcoal, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, glucose, ethanol, tamsulosin, glycerin, arginine, levocarnitine, cysteine, valproic acid, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone

Brigatinib Disease Interaction

Moderate: liver dysfunction, pulmonary toxicity, renal impairment

Volume of Distribution

The apparent volume of distribution at steady state is 153 L.

Elimination Route

Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC.

Half Life

The half-life of brigatinib at steady-state was 25 hours.

Clearance

After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h.

Elimination Route

The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine.

Pregnancy & Breastfeeding use

Based on its mechanism of action and findings in animals, Brigatinib can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of Brigatinib in pregnant women. There are no data regarding the secretion of Brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential for adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with Brigatinib and for 1 week following the final dose.

Storage Condition

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

Innovators Monograph

You find simplified version here Brigatinib