Application and Pharmacology of Brigatinib

Brigatinib (marketed as Alunbrig) is a small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals, Inc.Brigatinib acts as both a anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Application

Brigatinib is an orally available inhibitor of receptor tyrosine kinases anaplastic lymphoma kinase (ALK) and the epidermal growth factor receptor (EGFR) with potential antineoplastic activity. Brigatinib binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. In addition, AP26113 appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. EGFR is overexpressed in a variety of cancer cell types.

Pharmacology

Mechanism of Action

Tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases, including ALK, ROS1, insulinlike growth factor-1 receptor (IGF-1R), and FLT-3, as well as EGFR deletion and point mutations.

Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays.

Exhibited in vivo antitumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib.

Also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.

Absorption

Peak plasma time: 1-4 hr

Peak plasma concentration: 552 ng/mL (90 mg); 1452 ng/mL (180 mg)

AUC: 8165 ng·h/mL (90 mg); 20,276 ng·h/mL (180 mg)

Distribution

Protein bound: 66%

Vd: 153 L (steady-state)

Metabolism

Primarily metabolized by CYP2C8 and CYP3A4

Active metabolite: AP26123 is ~3-fold less potent than brigatinib

Elimination

Half-life: 25 hr

Oral clearance: 12.7 L/hr

Excretion: 65% feces; 25% urine (unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively)

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