Lung cancer is one of the most common malignant tumors in the world, with the highest fatality rate among all malignant tumors. Lung cancer is divided into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of lung cancer, including squamous cell carcinoma, adenocarcinoma and large cell undifferentiated carcinoma. SCLC accounts for only 15%. Compared with SCLC, NSCLC cancer cells grow and divide more slowly, and spread and metastasise relatively late. About 75% of patients with NSCLC are found in an advanced stage, and 5-year survival rates are poor. Anaplastic lymphoma kinase gene rearrangement is a fusion gene formed by chromosomal inversion of echinoderm microtubule-associated egg and ALK gene rearrangement in NSCLC patients (EML4-ALK), also known as ALK gene positivity, which is an important new tumor driver gene promoting the occurrence and progression of NSCLC, and its incidence accounts for 3%-5% of SCLC patients. Crizotinib, a first-generation ALK tyrosine kinase inhibitor developed by Pfizer, is an ATP-competitive tyrosinase inhibitor, which plays an important role in individualized targeted therapy of NSCLC. From 2011 to now, the National Comprehensive Cancer Network (NCCN) and the European Society of Oncology (ESMO) have issued guidelines for the diagnosis and treatment of NSCLC and recommended them as the first line of treatment for ALK+(positive)NSCLC. On August 28, 2011, it was approved to be marketed by the Food and Drug Administration (FDA) of the United States. On September 18, 2014, crizotinib capsules of two specifications were obtained the import registration certificate of the State Food and Drug Administration (CFDA) for the treatment of advanced or metastatic ALK+NSCLC. However, although crizotinib achieves good median progression-free survival (PFS) and objective response rate (ORR) in ALK+ patients, crizotinib cannot cross the blood-brain barrier and cannot treat ALK+ lung cancer in the central nervous system. In addition, NSCLC continues to generate new genetic subtypes, and eventually escape the fate of drug resistance and treatment failure. Brigatinib has been temporarily translated as bugitinib, while other translations include bugitinib, Britinib, bugitabine, etc.
Code AP26113, The chemical name was 5-chloro-N4- [2-(dimethylphosphoryl)phenyl] -N2-{2-methoxy-4 [4-(4-methylpiperazin-1-yl)piperidin-1-yl] phenyl}pyrimid Fine - 2, 4 - diamine; The Chinese chemical name is 5-chloro-N2 -{2-methoxy-4 - [4-(4-methylpiperazine-1) piperidine 1-] phenyl}-N4- [2-(dimethylphosphoacyl) phenyl] -2, 4-pyrimidine diamine. Bugatinib was originally developed by Ariad Pharmaceuticals of the United States, which was later acquired by Takeda Pharmaceuticals of Japan as a subsidiary of Takeda Pharmaceuticals to market and distribute it in the United States. Bugitinib is a new generation tyrosine kinase (TK) inhibitor, which has significant therapeutic effect on ALK+ metastatic NSCLC. On August 30, 2016, the US FDA granted Bugitinib the status of breakthrough therapy and rare drug for the treatment of ALK+NSCLC for patients who have progressed or cannot tolerate the first-generation treatment crizotinib, giving priority for marketing application review and allowing application data to be submitted on a rolling basis. The FDA approved bugatinib on April 28, 2017, under the trade name Alunbrigtm.
【 Pharmacological Effects 】[1]
Bouguer for, is a tyrosine kinase inhibitor in vitro and clinical can reach concentrations, for a variety of kinases, including ALK, ROS1 proto-oncogene (C - rosproto - oncogene1), insulin-like growth factor 1 receptor (insulin - likegrowthfactor1receptor, Igf-1r, FMS-like tyrosinekinase 3(FLT-3) and epidermal growth factor receptor (EGFR) deletion and point mutation showed inhibitory activity. In vitro and in vivo, bugatinib inhibited the phosphorylation of ALK itself and mediated the phosphorylation of downstream signaling proteins STAT3, AKT, ERK1/2 and S6. Bugitinib also inhibited the proliferation of EML4-ALK and NPM-ALK fusion protein cell lines in vitro and showed a dose-dependent effect on the growth of EML4-ALK+NSCLC xenografts in mice. Clinically, bugitinib inhibited the survival of eml4-alk expressing cells and 17 mutants in vitro at concentrations ≤500nmol• l-1, which are associated with resistance to ALK inhibitors. Crizotinib, EGFR-DEL (E746-A750), ROS1-L2026M, FLT3-F691L, FLT3-D835Y, etc. Bugatinib also showed antitumor activity in vivo against four EML4-ALK mutants, including G1202R and L1196M mutants isolated from plasma in NSCLC patients whose disease had progressed after crizotinib treatment. Bugitinib can reduce the ALK burden and prolong the survival of mice implanted intracranial with a driver tumor cell line.
【 Synthetic route 】 [2]
There are two synthesis routes of brigatinib reported in the literature:
Route 1, 5-fluoro-2-nitrophenyl ether as the starting material, by 1-methyl-4 -(piperidine-4-yl) piperazine substitution, catalytic hydrogenation, guanidine mono-cyanamide, N, The target compound brigatinib was obtained by cyclization of N-dimethyl aminoacrylate, condensation with 2-(dimethyl phosphoyl) aniline (8) and chlorination with N-chlorinated succinimide (NCS). The linear synthesis method was adopted in this route, and the yield was low. Moreover, the expensive organic base 1, 8-diazodicyclic undecarbo7-ene (DBU) and the condensation agent benzotriazole-1-oxy trioxyl (dimethylamino) phosphoonium hexafluorophosphate (BOP) were used in the condensation reaction, which increased the production cost and made the product difficult to purify.
The second route was to obtain the intermediate 2, 5-dichloro-N -(2-(dimethylphosphonoyl) phenyl) pyrimidine-4-amine (9) by o-iodoaniline coupling and 2, 4, 5-trichloropyrimidine substitution. The intermediate 2-methoxy-4 - [4-(4-methylpiperazine-1-yl) piperidine-1-yl] aniline (5) was obtained from 5-fluoro-2-nitrophenyl ether by 1-methyl-4 -(piperidine-4-yl) piperidine-4-yl) piperazine substitution and catalytic hydrogenation. Intermediates 5 and 9 undergo substitution reaction to obtain the target product brigatinib. The raw materials used in this route are expensive, the production cost is high, and some intermediates need to be purified by column chromatography, so it is not suitable for large-scale production.
FIG. 1 Synthesis route of bougatinib
The new synthesis route of brigatinib: using diethyl phosphite as the starting material, and methyl magnesium chloride through grignard reaction to prepare dimethylphosphine (7), and then coupled with o-iodoaniline to obtain intermediate 8,8 and 2, 4, 5-trichloropyrimidine substitution reaction to obtain intermediate 9; The intermediate 1-(3-methoxy-4-nitrophenyl) piperidine-4-ketone (3) was prepared by the substitution reaction of 5-fluoro-2-nitrophenyl (2) and 4-piperidine-4-ketone (2) as the starting material. Intermediate 3 and N-methylpiperazine were reduced by amination reaction to yield intermediate 1-(1-(3-methoxy-4-nitrophenyl) piperidine 4-yl) -4-methylpiperazine (4), 4 by hydrazine hydrate reaction to yield intermediate 5; Intermediates 5 and 9 are substituted to obtain brigatinib. The synthesis route is shown in Figure 1.
[Pharmacokinetics] [1]
1. The absorption
After a single oral administration of 30 to 240mg of bugatinib, the median tmax to reach Cmax was 1 to 4 hours. In healthy subjects, a high-fat diet (approximately 3.85 kJ, containing 58g carbohydrate, 59g fat, and 40g protein) followed by medication resulted in a 13% reduction in Cmax and no effect on AUC compared with overnight fasting.
The binding rate of bugitinib to human plasma protein was 66%. In vitro, the binding rate was independent of drug concentration. The ratio of blood to plasma concentration was 0.69. Bugitinib 180mg orally once a day, the mean steady-state apparent distribution volume (Vz/F) was 153L.
The mean steady-state apparent oral clearance rate (CL/F) was 12.7 L•h-1, and the mean plasma elimination half-life (t1/2) was 25h.
Metabolism of 2.
In vitro, bugatinib is mainly metabolized by CYP2C8 and CYP3A4 enzymes. Healthy subjects received a single oral dose of 180mg of radiolabelated bugatinib, and the two major metabolic pathways were n-demethylation and conjugation to cysteine. The unaltered protodrug and its major metabolite AP26123 were the major radioactive components in the circulation, accounting for 92% and 3.5%, respectively. At steady state, the AUC of AP26123 was less than 10% of that of bugatinib. In vitro, the activity of metabolite AP26123 against ALK was about 33.3% of that of bugatinib.
3. The discharge
Healthy subjects received a single oral dose of 180mg of radiolabelated bugatinib with 65% fecal recovery and 25% urine recovery.
4. Pharmacokinetics in special populations
① Patients with liver injury: liver elimination is the main way of bugitinib excretion, and liver injury may increase the concentration of bugitinib in blood. According to a population pharmacokinetic analysis, 49 subjects with mild liver injury (total bilirubin (T-BIL) within the upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or T-Bil > 1 to 1.5 times ULN and AST as any value), Compared with 377 subjects with normal liver function (both T-Bil and AST were normal), bougatinib exposure in the two groups was similar. The pharmacokinetics of bugitinib have not been studied in patients with moderate (T-bil > 1.5 to 3.0 times ULN and AST, any value) or severe (T-Bil > 3.0 times ULN and AST, any value) liver damage.
② patients with renal injury: according to a population pharmacokinetic analysis, 125 subjects had mild renal injury [creatinine clearance rate (CLcr)60 to < 90mL•min-1], Compared with 270 subjects with normal renal function (CLcr≥90mL•min-1), 34 subjects with moderate renal impairment (CLcr30 to < 60mL•min-1) had similar exposure to bugatinib, suggesting that dose adjustment was not necessary in patients with mild to moderate renal impairment. Clinical trials have not included patients with severe renal injury (CLcr < 30mL•min-1).
【 Indications 】[1]
Bugitinib is indicated for patients with ALK-positive metastatic NSCLC who cannot tolerate crizotinib treatment or whose disease has progressed. The indication was accelerated based on the rate of tumor response and the duration of response, and subsequent approval of the indication may depend on confirmation in further clinical trials and description of clinical benefit.
[1] Dose and method of taking
Alunbrig is a film coated tablet available in 2 sizes, 30 mg and 90mg each.
Recommended dosage and method of Taking The medicine can be taken with or without food. The medicine should be swallowed whole, not crushed or chewed. If one dose is missing or vomiting occurs after taking the medicine, do not take the additional dose on the same day, should take the next dose according to the medication schedule. The normal dose was 90mg orally once a day during the induction period of the first 7 days. If the patient could tolerate it, the dose was increased to 180mg once a day until the disease progressed or the adverse reactions of the drug could not be tolerated.
Adjust the dose to adjust the dose of adverse reactions, if taking 90mg, once a day. The first dose can be reduced to 60mg, once a day, and if adverse reactions occur again, the drug will be permanently discontinued. If you are taking 180mg once a day. The first dose was 120mg once a day, the second dose was 90mg once a day, and the third dose was 60mg once a day. Due to adverse reactions, the dose can not be increased at will. If 60mg is not tolerated, the once-daily dose should be permanently discontinued.
