Brigatinib

584.102

583.259155

HYW8DB273J

C98831

L01XE43|L - Antineoplastic and immunomodulating agents

85.9

4.6

1.31±0.1 g/cm3(Predicted)

781.8±70.0 °C(Predicted)

426.6±35.7 °C

1.641

H2O: Insoluble

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P281, P301+P310, P308+P313, P314, P321, P330, P391, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

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.

In preregistration trials of brigatinib, ALT elevations occurred in up to 40% of patients but values above 5 times the upper limit of normal (ULN) were found in only 1% to 3%. Brigatinib therapy was also associated with frequent elevations in alkaline phosphatase (15% to 29%), but the serum enzyme elevations were usually mild-to-moderate in degree as well as asymptomatic and transient in nature. Clinically apparent liver injury with jaundice was not reported in the prelicensure studies of brigatinib and no reports have been published since its approval. In general, the ALK kinase inhibitors are associated with a high rate of serum enzymes elevations during therapy, but convincing cases of idiosyncratic, clinically apparent liver injury from their use have been rare. Most cases have been reported with crizotinib [approved in 2011] which is also the most frequently used of the kinase inhibitors with activity against ALK. Cases of liver injury with jaundice were reported to occur in trials of alectinib [2015] and ceritinib [2014], but details were not provided. Thus, acute liver injury with jaundice may occur with brigatinib but it must be rare if it occurs at all.

66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69.

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. 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. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. 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.|FDA Label|Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase (ALK)‑positive advanced non‑small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor.Alunbrig is indicated as monotherapy for the treatment of adult patients with anaplastic lymphoma kinase ALKpositive advanced NSCLC previously treated with crizotinib.|Treatment of anaplastic large cell lymphoma, Treatment of inflammatory myofibroblastic tumours, Treatment of non-small cell lung cancer|Drug: Brigatinib

Brigatinib is a tyrosine kinase receptor inhibitor and antineoplastic agent used in the therapy of selected forms of advanced non-small cell lung cancer. Brigatinib is associated with a moderate rate of transient elevations in serum aminotransferase levels during therapy but has yet to be linked to instances of clinically apparent acute liver injury.

Antineoplastic Agents

Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still unknown.

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.|The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine.|The apparent volume of distribution at steady state is 153 L.|After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h.

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.

The half-life of brigatinib at steady-state was 25 hours.

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.

Alunbrig

Human drugs -> Alunbrig -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients