Brigatinib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

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

Brigitanib inhibits the proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden, and prolonged survival in mice EML4-ALK xenograft models. The Time course of Brigatinib and exposure-response studies are still unknown.

or

Brigatinib is an inhibitor of ALK and mutated EGFR. ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.

Brigatinib inhibits ROS proto-oncogene-1 fusions and EGFR mutations and has a remarkable effect on the central nervous system.[rx] Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Additionally, the T790M “gatekeeper” mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors.[rx] While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.

Indications

  • The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression, and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation, and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confers resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib.
  • Brigatinib is a tyrosine kinase receptor inhibitor and antineoplastic agent used in the therapy of selected forms of advanced non-small cell lung cancer
  • Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non‑small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.
  • Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase ALKpositive advanced NSCLC previously treated with crizotinib.
  • Metastatic Non-Small Cell Lung Cancer

Use in Cancer

Brigatinib is approved to treat:

  • Non-small cell lung cancer that is ALK-positive and has metastasized (spread to other parts of the body). It is used in adults.

Brigatinib is also being studied in the treatment of other types of cancer.

Contraindications

  • high blood pressure
  • slow heartbeat
  • high amount of bilirubin in the blood
  • high blood sugar
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • increased creatine kinase levels
  • lung tissue problem
  • high blood levels of the lipase enzyme
  • high blood levels of the amylase enzyme
  • chronic kidney disease stage 4 (severe)
  • kidney disease with likely reduction in kidney function
  • Child-Pugh class C liver impairment

Dosage

Strengths: 90 mg; 30 mg; 180 mg; 90 mg-180 mg

Non-Small Cell Lung Cancer

  • Initial dose: 90 mg orally once a day for the first 7 days
    Maintenance dose: 180 mg orally once a day
  • Patients should be selected for the treatment of metastatic NSCLC based on the presence of ALK positivity in tumor specimens.
  • FDA-approved test for the detection of ALK rearrangements in NSCLC is available at http://www.fda.gov/CompanionDiagnostic
  • Treatment should be continued until the disease progresses or has unacceptable toxicity.

Renal Dose Adjustments

  • Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment is recommended.
  • Severe renal dysfunction (CrCl 15 to 29 mL/min): Reduce once-daily dose by approximately 50% (i.e., from 180 mg to 90 mg OR 90 mg to 60 mg).

Liver Dose Adjustments

  • Mild to moderate liver dysfunction (Child-Pugh A to B): No adjustment recommended.
  • Severe liver dysfunction (Child-Pugh C): Reduce once-daily dose by approximately 40% (i.e., from 180 mg to 120 mg, OR 120 mg to 90 mg, OR 90 mg to 60 mg).

Dose Adjustments

DOSE REDUCTION FOR ADVERSE REACTIONS:
STARTING DOSE 90 MG ONCE A DAY:

  • First reduction: 60 mg once a day
  • Second reduction: Permanently discontinue therapy.
  • Third reduction: N/A

STARTING DOSE 180 MG ONCE A DAY:

  • First reduction: 120 mg once a day
  • Second reduction: 90 mg once a day
  • Third reduction: 60 mg once a da
  • Once the dose is reduced, do not subsequently increase the dose.
  • Permanently discontinue this drug if patients are unable to tolerate 60 mg once a day.
  • Dosing interruption of 14 days or longer (for reasons other than adverse reactions): Resume at 90 mg once a day for 7 days before increasing to the previously tolerated dose.

STRONG OR MODERATE CYP450 3A INHIBITORS:

  • Avoid concomitant use.
  • If concomitant use of a strong CYP450 3A inhibitor cannot be avoided, reduce the once-a-day dose of this drug by approximately 50% (i.e., from 180 mg to 90 mg OR from 90 mg to 60 mg).
  • If coadministration of a moderate CYP450 3A inhibitor cannot be avoided, reduce the once-daily dose of this drug by approximately 40% (i.e., from 180 mg to 120 mg, OR 120 mg to 90 mg, OR from 90 mg to 60 mg).
  • After discontinuation of a strong or moderate CYP450 3A inhibitor, resume the dose of this drug that was tolerated prior to initiating the CYP450 3A inhibitor.

MODERATE CYP450 3A INDUCERS:

  • Avoid concomitant use.
  • If coadministration of a moderate CYP450 3A inducer cannot be avoided, increase the once-daily dose of this drug in 30 mg increments after 7 days of therapy with the current dose as tolerated, up to a maximum of twice the dose that was tolerated prior to initiating the moderate CYP450 3A inducer.
  • After discontinuation of a moderate CYP450 3A inducer, resume the dose of this drug that was tolerated prior to initiating the moderate CYP450 3A inducer.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:
GRADE 1:

  • If new pulmonary symptoms occur during the first 7 days of therapy, withhold this drug until recovery to baseline, then resume at the same dose and do not escalate to 180 mg if ILD/pneumonitis is suspected.
  • If new pulmonary symptoms occur after the first 7 days of therapy, withhold this drug until recovery to baseline, then resume at same dose.
  • If ILD/pneumonitis recurs, permanently discontinue this drug.

GRADE 2:

  • If new pulmonary symptoms occur during the first 7 days of therapy, withhold this drug until recovery to baseline; resume at the next lower dose and do not dose escalate if ILD/pneumonitis is suspected.
  • If new pulmonary symptoms occur after the first 7 days of therapy, withhold this drug until recovery to baseline.
  • If ILD/pneumonitis is suspected, resume at the next lower dose; otherwise, resume at the same dose.
  • If ILD/pneumonitis recurs, permanently discontinue this drug.

Grade 3 or 4:

  • Permanently discontinue this drug.

HYPERTENSION:
*GRADE 3 (SBP 160 mmHg or greater or DBP 100 mmHg or greater, medical intervention indicated, more than 1 antihypertensive drug, or more intensive therapy than previously used indicated):

  • Withhold dosing until recovery to Grade 1 or less (SBP less than 140 mmHg and DBP less than 90 mmHg) then resume at the next lower dose.
  • Recurrence: Withhold the drug until recovery to Grade 1 or less and resume at next lower dose or permanently discontinue this drug.

GRADE 4 (life-threatening consequences, urgent intervention indicated):

  • Withhold this drug until recovery to Grade 1 or less and resume at the next lower dose OR permanently discontinue this drug.
  • GRADE 4 RECURRENCE: Permanently discontinue this drug.

BRADYCARDIA (HR less than 60 bpm):
*SYMPTOMATIC BRADYCARDIA:

  • Withhold this drug until recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.
  • If a concomitant medication known to cause bradycardia is identified and discontinued or dose-adjusted, resume this drug at the same dose upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above.
  • If no concomitant medication known to cause bradycardia is identified, or if contributing concomitant medications are not discontinued or dose-adjusted, resume this drug at next lower dose upon recovery to asymptomatic bradycardia or to resting heart rate of 60 bpm or above.

LIFE-THREATENING BRADYCARDIA (urgent intervention indicated):

  • Permanently discontinue this drug if no contributing concomitant medication is identified.
  • If contributing concomitant medication is identified and discontinued or dose-adjusted, resume this drug at next lower dose upon recovery to asymptomatic bradycardia or to a resting heart rate of 60 bpm or above, with frequent monitoring as clinically indicated.
  • Recurrence: Permanently discontinue this drug.

VISUAL DISTURBANCE:

  • GRADE 2 OR 3: Withhold this drug until recovery to Grade 1 or baseline, then resume at the next lower dose.
  • GRADE 4: Permanently discontinue this drug.

CREATINE PHOSPHOKINASE (CPK) ELEVATION:
*GRADE 3 OR 4 CPK ELEVATION (greater than 5 times upper level of normal [ULN] with Grade 2 or higher muscle pain or weakness):

  • Withhold this drug until recovery to Grade 1 or less ((less than or equal to 2.5 x ULN) or to baseline, then resume at the same dose.
  • Recurrence: Withhold until recovery to Grade 1 or less (less than or equal to 2.5 x ULN) or to baseline, then resume at the next lower dose

LIPASE/AMYLASE ELEVATION:

  • GRADE 3 (greater than 2 x ULN): Withhold this drug until recovery to Grade 1 or less (1.5 x ULN or less) or to baseline, then resume at the same dose.
  • RECURRENCE: Withhold until recovery to Grade 1 or less (less than or equal to 1.5 x ULN) or to baseline, then resume at the next lower dose.
  • GRADE 4 (greater than 5 x ULN): Withhold dosing until recovery to Grade 1 or less (1.5 x ULN or less) or to baseline, then resume at the next lower dose.

HYPERGLYCEMIA:
*GRADE 3 (greater than 250 mg/dL OR 13.9 mmol/L) OR GRADE 4:

  • Withhold this drug until adequate hyperglycemic control is achieved and resume at the next lower dose OR permanently discontinue therapy.

OTHER ADVERSE REACTIONS:
*GRADE 3:

  • Withhold this drug until recovery to baseline, then resume at the same dose.
  • Recurrence: Withhold this drug until recovery to baseline, then resume at the next lower dose OR discontinue therapy.

*GRADE 4:

  • Withhold dosing until recovery to baseline, then resume at the next lower dose.
  • Recurrence: Permanently discontinue therapy.

Side Effects

The Most Common

  • nausea
  • diarrhea
  • vomiting
  • constipation
  • tiredness
  • rash
  • headache
  • numbness, pain, tingling, or burning feeling in the feet or hands
  • back or joint pain
  • loss of appetite
  • difficulty falling asleep or staying asleep

More Common

  • shortness of breath or difficulty breathing
  • chest pain
  • cough with or without mucus
  • fever
  • headache, dizziness, lightheadedness, or feeling faint
  • blurred or double vision
  • seeing flashes of light
  • light hurting your eyes
  • seeing ”floaters” or small specks
  • extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness
  • upper stomach pain that may spread to the back or get worse with eating; weight loss; or nausea
  • slow or irregular heartbeat
  • muscle pain, spasms, tenderness, or weakness

Rare

  • lung problems–cough, trouble breathing, chest pain, fever;
  • vision problems–blurred vision, double vision, increased sensitivity to light, seeing flashes of light or “floaters” in your vision;
  • high blood pressure–severe headache, pounding in your neck or ears, dizziness;
  • high blood sugar–increased thirst, increased urination, hunger, nausea, fruity breath odor, weakness, confusion;
  • heart problems–very slow heartbeats, feeling like you might pass out;
  • muscle problems–unexplained muscle pain or weakness; or
  • pancreatitis–upper stomach pain (worse with eating and may spread to your back), nausea, weight loss.

Drug Interaction

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on its mechanism of action and findings in animals, brigatinib can cause fetal harm when administered to pregnant women. Based on findings in male reproductive organs in animals, brigatinib may cause reduced fertility in males.

Females of reproductive potential are advised to use effective nonhormonal contraception during treatment with brigatinib and for at least 4 months after the final dose. Brigatinib can render some hormonal contraceptives ineffective. Because of the potential for genotoxicity, males with female partners of reproductive potential are advised to use effective contraception during treatment with brigatinib and for at least 3 months after the final dose.

Lactation

It is unknown if brigatinib is distributed in human breast milk. Because of the potential for adverse reactions in breastfed infants, lactating women are advised not to breastfeed during treatment with brigatinib and for 1 week following the final dose.

How should this medicine be used?

Brigatinib comes as a tablet to take by mouth. It is usually taken with or without food once daily. Take brigatinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take brigatinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not chew or crush them.

If you vomit after taking brigatinib, do not take another dose. Continue your regular dosing schedule.

Your doctor may start you on a low dose of brigatinib and increase your dose once after 7 days of treatment.

Your doctor may need to temporarily or permanently stop your treatment or decrease your dose of brigatinib or other medications that you are taking, depending on the side effects that you experience during your treatment. Talk to your doctor about how you are feeling during your treatment. Do not stop taking brigatinib without talking to your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before taking brigatinib,

  • tell your doctor and pharmacist if you are allergic to brigatinib, any other medications, or any of the ingredients in brigatinib tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: antifungals such as itraconazole (Onmel, Sporanox, Tolsura), ketoconazole, buprenorphine and naloxone (Suboxone), carbamazepine (Equetro, Tegretol, Teril, others), clarithromycin, cyclosporine (Gengraf, Neoral, Sandimmune), diltiazem (Cardizem, Cartia, Diltzac, others), efavirenz (Sustiva, in Atripla, Symfi), erythromycin (E.E.S., Eryc, Erythrocin), indinavir (Crixivan), nefazodone, nelfinavir (Viracept), nevirapine (Viramune), phenobarbital; phenytoin (Dilantin, Phenytek), pioglitazone (Actos, in Actoplus Met, Duetact, Oseni), rifabutin (Mycobutin), rifampin (Rifadin, Rimactane, in Rifamate, in Rifater), ritonavir (Norvir, in Kaletra, Technivie, Viekira), sirolimus (Rapamune), tacrolimus (Astagraf, Envarsus, Prograf), or verapamil (Calan, Verelan, in Tarka). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with brigatinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor what herbal products you are taking, especially St. John’s wort.
  • tell your doctor if you have or have ever had high blood pressure; a slow heartbeat; diabetes or other blood sugar problems; or kidney or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or plan to father a child. Brigatinib may interfere with the action of hormonal contraceptives (birth control pills, patches, rings, implants, or injections), so you should not use these as your only method of birth control during your treatment. You must use a non-hormonal birth control such as a barrier method (device that blocks sperm from entering the uterus such as a condom or a diaphragm). Ask your doctor to help you choose a method of birth control that will work for you. If you are female, you will need to use non-hormonal birth control during your treatment and for 4 months after your final dose. If you are male, you and your female partner should use birth control during your treatment and continue to use birth control for 3 months after your final dose. Brigatinib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed during your treatment with brigatinib and for up to 1 week after your final dose.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of taking brigatinib.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Brigatinib
  2. https://go.drugbank.com/drugs/DB12267
  3. https://en.wikipedia.org/wiki/Brigatinib
  4. https://medlineplus.gov/druginfo/meds/a617016.html
  5. https://www.drugs.com/mtm/brigatinib.html
  6. https://www.cancer.gov/about-cancer/treatment/drugs/brigatinib
  7. Guide to Pharmacology Target Classification
  8. ChemIDplus Chemical Information Classification
  9. CompTox Chemicals Dashboard Chemical Lists
  10. NCI Thesaurus Tree
  11. PubChem
  12. LICENSE
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