Brigatinib

Oral
Metastatic non-small cell lung carcinoma

Patients taking strong CYP3A4 inhibitors: Reduce dose by approx 50%, resume to usual dose upon discontinuation of treatment.

Severe (eGFR <30 mL/min): 60 mg once daily for 7 days, then increased to 90 mg once daily.

Severe (Child-Pugh class C): 60 mg once daily for 7 days, then increased to 120 mg once daily.

film-coated tab: May be taken with or without food. Swallow whole, do not chew/crush.

Pregnancy and lactation. Concomitant use with moderate and strong CYP3A4 inducers e.g. rifampicin, St. John’s wort, grapefruit or grapefruit juice.

Concomitant use with strong CYP3A4 inhibitors. Renal and hepatic impairment.

Significant: Cardiac effects (e.g. hypertension), visual disturbances (e.g. blurred vision, diplopia, reduced visual acuity, macular oedema, cataract), hyperglycaemia; elevations of CPK, pancreatic enzymes (e.g. lipase and amylase), hepatic enzymes (e.g. AST/ALT) and bilirubin.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Palpitations, tachycardia, chest discomfort.
Gastrointestinal disorders: Nausea, diarrhoea, vomiting, constipation, abdominal pain, dry mouth, dyspepsia, stomatitis, flatulence.
General disorders and admin site conditions: Fatigue, oedema, pyrexia, pain.
Infections and infestations: Pneumonia.
Investigations: ECG QT prolonged, weight decreased, increased alkaline phosphatase and blood lactate dehydrogenase, elevated blood creatinine, increased APTT, decreased neutrophil, lymphocyte, platelet, and WBC counts.
Metabolism and nutrition disorders: Decreased appetite, hypokalaemia, hyponatraemia, hypophosphataemia, hypomagnesaemia, hypercalcaemia, hyperinsulinaemia.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, pain in extremity.
Nervous system disorders: Headache, dizziness, dysgeusia, peripheral neuropathy, memory impairment.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Cough, dyspnoea, non-cardiac chest pain, upper respiratory tract infection.
Skin and subcutaneous tissue disorders: Rash, pruritus, dry skin, photosensitivity.
Potentially Fatal: Pulmonary toxicity (e.g. interstitial lung disease or pneumonitis), bradycardia.

This drug may cause dizziness, visual disturbances or fatigue, if affected, do not drive or operate machinery.

Establish ALK positivity. Monitor blood pressure and heart rate after 2 weeks and at least monthly thereafter; creatine phosphokinase (CPK) and amylase/lipase levels periodically during treatment; fasting serum glucose at baseline and periodically thereafter. Assess for signs/symptoms of interstitial lung disease (ILD) or pneumonitis, muscular symptoms of CPK elevations, and visual disturbances.

Decreased plasma concentration and efficacy with strong CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital), and moderate CYP3A4 inducers (e.g. efavirenz, modafinil, bosentan, etravine, nafcillin). Increased plasma concentration with strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, indinavir, nelfinavir, ritonavir, clarithromycin, telithromycin, troleandomycin, mibefradil, nefazodone). Increased risk of bradycardia with antihypertensive agents. May reduce plasma levels and efficacy of CYP3A substrates (e.g. alfentanil, fentanyl, quinidine, ciclosporin, tacrolimus, hormonal contraceptives). May increase plasma concentrations of transporter substrates (e.g. digoxin, dabigatran, colchicine, pravastatin, methotrexate, rosuvastatin, sulfasalazine).

Avoid grapefruit or grapefruit juice as it may increase brigatinib plasma concentrations. Avoid St. John’s wort as it may decrease brigatinib plasma concentrations.

Description:
Mechanism of Action: Brigatinib is a multiple tyrosine kinases inhibitor with activity against anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), insulin-like growth factor-1 receptor (IGF-1R), fms-like tyrosine kinase-3 (FLT-3), and epidermal growth factor receptor (EGFR) deletion and point mutations. It inhibits the autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: Approx 1-4 hours.
Distribution: Volume of distribution: 153 L. Plasma protein binding: 91%.
Metabolism: Metabolised in the liver mainly via N-demethylation and cysteine conjugation by CYP2C8 and CYP3A4 isoenzymes to form its primary N-desmethyl brigatinib (AP26123) metabolite.
Excretion: Mainly via faeces (65%; 41% as unchanged drug); urine (25%; 86% as unchanged drug). Elimination half-life: 25 hours.

Source: National Center for Biotechnology Information. PubChem Database. Brigatinib, CID=68165256, https://pubchem.ncbi.nlm.nih.gov/compound/Brigatinib (accessed on Jan. 21, 2020)

Store between 20-25°C. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.

Targeted Cancer Therapy

L01ED04 - brigatinib ; Belongs to the class of anaplastic lymphoma kinase (ALK) inhibitors. Used in the treatment of cancer.

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Buckingham R (ed). Brigatinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/09/2019.

Joint Formulary Committee. Brigatinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/09/2019.