Product Information
Registration Status: ActiveALUNBRIG FILM-COATED TABLET 30mg is approved to be sold in Singapore with effective from 2019-04-04. It is marketed by TAKEDA PHARMACEUTICALS (ASIA PACIFIC) PTE LTD, with the registration number of SIN15658P.
This product contains Brigatinib 30mg in the form of TABLET, FILM COATED. It is approved for ORAL use.
This product is manufactured by PENN PHARMACEUTICAL SERVICES LIMITED in UNITED KINGDOM.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Description
Brigatinib, originally named AP26113, is a reversible dual inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR). It presents selectivity against the mutant forms of EGFR compared to the wild-type.[A31311] It also exhibits selectivity against 9 different Crizotinib-resistant mutants of the EML4-ALK fusion gene, which is a pivotal player in the transformation of susceptible lung parenchyma.[A31313] Brigatinib was developed by Ariad Pharmaceuticals, a subsidiary of Takeda Pharmaceutical Company Limited, and FDA-approved on April 28, 2017.[L1026]
Indication
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.[A31311] 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.[A31313] The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival.[A31316] Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib.[A31314]
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 against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins.[A31319]
Pharmacokinetics
- Absorption
- Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC.[A31320]
- Distribution
- The apparent volume of distribution at steady state is 153 L.[A31320]
- Metabolism
- Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower.[L1028]
- Elimination
Clearance
After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h.[L1028]
Toxicity
Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis.[FDA label]
Active Ingredient/Synonyms
Brigatinib | Brigatinib |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.