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. Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.
Absorption: Following administration of single oral doses of Brigatinib of 30 to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Distribution: Brigatinib is 66% bound to human plasma proteins and the binding is not concentration-dependent in vitro. The blood to plasma concentration ratio is 0.69. Following oral administration of Brigatinib 180 mg once daily, the mean apparent volume of distribution (Vz/F) of Brigatinib at steady-state was 153 L.
Elimination: Following oral administration of Brigatinib 180 mg once daily, the mean apparent oral clearance (CL/F) of Brigatinib at steady-state is 12.7 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism: Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled Brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged Brigatinib (92%) and its primary metabolite, AP26123 (3.5%), were the major circulating radioactive components. The steady-state AUC of AP26123 was less than 10% of AUC of Brigatinib exposure in patients. The metabolite, AP26123, inhibited ALK with approximately 3-fold lower potency than Brigatinib in vitro.
Excretion: Following oral administration of a single 180 mg dose of radiolabeled Brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged Brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.
Drugs that may Increase Brigatinib Plasma Concentrations: Strong CYP3A Inhibitors: Coadministration of Itraconazole, a strong CYP3A inhibitor, increased Brigatinib plasma concentrations and may result in increased adverse reactions. Concomitant use of strong CYP3A inhibitors with Brigatinib, including but not limited to certain Antivirals (e.g., Boceprevir, Cobicistat, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir), Macrolide antibiotics (e.g., Clarithromycin), Antifungals (e.g., Itraconazole, Ketoconazole, Posaconazole, Voriconazole), and Conivaptan should be avoided. Grapefruit or grapefruit juice should be avoided as it may also increase plasma concentrations of Brigatinib. If concomitant use of a strong CYP3A inhibitor cannot be avoided, the dose of Brigatinib should be reduced by approximately 50%.
Drugs that may Decrease Brigatinib Plasma Concentrations: Strong CYP3A Inducers: Coadministration of Brigatinib with Rifampin, a strong CYP3A inducer, decreased Brigatinib plasma concentrations and may result in decreased efficacy. Concomitant use of strong CYP3A inducers with Brigatinib should be avoided, including but not limited to Rifampin, Carbamazepine, Phenytoin, and St. John's Wort.
Drugs that may have their Plasma Concentrations altered by Brigatinib: CYP3A Substrates: Brigatinib induces CYP3A in vitro and may decrease concentrations of CYP3A substrates. Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.
Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.
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