ot been studied [see CLINICAL PHARMACOLOGY (12.3)].
8.7 Renal Impairment
No dose adjustment is recommended for patients with mild and moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault)]. The pharmacokinetics and safety of ALUNBRIG in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by Cockcroft-Gault) have not been studied [see CLINICAL PHARMACOLOGY (12.3)].
11 DESCRIPTION
Brigatinib is a kinase inhibitor. The chemical name for brigatinib is 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine. The molecular formula is C29H39ClN7O2P which corresponds to a formula weight of 584.10 g/mol. Brigatinib has no chiral centers. The chemical structure is shown below:
Chemical Structure
Brigatinib is an off-white to beige/tan solid. The pKas were determined to be: 1.73 ± 0.02 (base), 3.65 ± 0.01 (base), 4.72 ± 0.01 (base), and 8.04 ± 0.01 (base).
ALUNBRIG is supplied for oral use as film-coated tablets containing 30 mg or 90 mg of brigatinib and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (Type A), magnesium stearate, and hydrophobic colloidal silica. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like 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. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.
12.2 Pharmacodynamics
Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
Cardiac Electrophysiology
The QT interval prolongation potential of ALUNBRIG was assessed in 123 patients following once daily ALUNBRIG doses of 30 mg (1/6th of the approved 180 mg dose) to 240 mg (1.3 times the approved 180 mg dose). ALUNBRIG did not prolong the QT interval to a clinically relevant extent.
12.3 Pharmacokinetics
The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at ALUNBRIG doses of 90 mg and 180 mg once daily was 552 (65%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 ( |
