Bosutinib is primarily metabolized by CYP3A4. The major circulating metabolites identified in plasma are oxydechlorinated (M2) bosutinib (19% of parent exposure) and N-desmethylated (M5) bosutinib (25% of parent exposure), with bosutinib N-oxide (M6) as a minor circulating metabolite. All the metabolites were deemed inactive.
In large clinical trials of bosutinib, elevations in serum aminotransferase levels were common, occurring in up to 58% of bosutinib treated patients. Values greater than 5 times the upper limit of normal (ULN) occurred in 4% to 19% of bosutinib recipients (and 3% of imatinib treated subjects). These abnormalities were usually asymptomatic, but led to discontinuation of therapy in up to 2% of treated patients. In addition, there have been isolated reports of clinically apparent liver injury attributed to bosutinib therapy, although the frequency of this outcome and the clinical features of the injury have not been well defined. The time to onset has generally been within 3 months and the pattern of serum enzyme elevations was usually hepatocellular.
Certainly other tyrosine kinase receptor inhibitors used in the therapy of CML such as imatinib, nilotinib and ponatinib have been associated with cases of acute liver injury with jaundice. With these agents, the liver injury typically arises after several months of therapy and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features (rash, fever and eosinophilia) and autoantibody formation are usually not present.
Reactivation of hepatitis B has been reported with imatinib and nilotinib therapy, but not with bosutinib. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir. Whether reactivation occurs with bosutinib therapy is unclear.
Likelihood score: D (possible uncommon cause of clinically apparent liver injury).
◉ Summary of Use during Lactation:No information is available on the clinical use of bosutinib during breastfeeding. Because bosutinib is 96% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 22 hours and it might accumulate in the infant. National Comprehensive Cancer Network guidelines recommend avoiding breastfeeding during bosutinib therapy and the manufacturer recommends withholding breastfeeding until 2 weeks following the last dose.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
94% bound to human plasma proteins in vitro. 96% bound to human plasma proteins in healthy subjects ex vivo. Extent of protein binding is not concentration-dependent.
Food increase the exposure of bosutinib. Tmax, single dose, cancer patients, fed-state = 4-6 hours; After 15 daily doses of bosutinib 500 mg with food in CML patients, the pharmacokinetic parameters are as follows: Cmax = 200 ng/mL; AUC = 3650 ng∙h/mL
来源:DrugBank
吸收、分配和排泄
消除途径
单次口服给药后，91.3%的剂量在粪便中回收，3%的剂量在尿液中回收。
When given a single oral dose, 91.3% of the dose was recovered in feces and 3% of the dose recovered in urine.
来源:DrugBank
吸收、分配和排泄
分布容积
表观分布容积 = 6080 ± 1230 L。
Apparent volume of distribution = 6080 ± 1230 L.
来源:DrugBank
吸收、分配和排泄
清除
单次口服剂量，饱腹状态下的平均清除率（CL/F）= 189 L/h
Mean clearance (CL/F), single oral dose, fed-state = 189 L/h
Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity
摘要：
Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of la led to le, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of le with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c, with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC50 of 1.2 nM in the Src enzymatic assay, an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.
[EN] BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME<br/>[FR] LIGANDS DE TYROSINE-KINASE BCR-ABL CAPABLES DE SE DIMÉRISER DANS UNE SOLUTION AQUEUSE, ET PROCÉDÉS D'UTILISATION DE CEUX-CI
申请人：COFERON INC
公开号：WO2015106292A1
公开（公告）日：2015-07-16
Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.
This invention relates to compounds of the formula (I):The invention also relates to processes for the preparation of the compound of the formula (I), pharmaceutical agents or compositions containing the compound or a method of using the compound for the treatment of proliferative diseases, such as cancer.
[EN] COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF SHP2<br/>[FR] COMPOSÉS ET COMPOSITIONS POUR INHIBER L'ACTIVITÉ DE SHP2
申请人：NOVARTIS AG
公开号：WO2016203404A1
公开（公告）日：2016-12-22
The present invention relates to compounds of formula I. The compounds are inhibitors of the Src Homolgy-2 phosphatase (SHP2) and thus useful in the treatment of Noonan Syndrome, Leopard Syndrome and cancer.
[EN] NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS<br/>[FR] NOUVEAUX COMPOSÉS 2-PIPERIDIN-1-YL-ACETAMIDE UTILISABLES EN TANT QU'INHIBITEURS DE TANKYRASE
申请人：NOVARTIS AG
公开号：WO2013012723A1
公开（公告）日：2013-01-24
The present invention provides for compounds of formula (I), wherein R1-R5 and L are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.
[EN] ANTIBODY CONJUGATES COMPRISING TOLL-LIKE RECEPTOR AGONIST AND COMBINATION THERAPIES<br/>[FR] CONJUGUÉS D'ANTICORPS COMPRENANT UN AGONISTE DU RÉCEPTEUR DE TYPE TOLL ET POLYTHÉRAPIES
申请人：NOVARTIS AG
公开号：WO2018198091A1
公开（公告）日：2018-11-01
Provided herein are antibody conjugates comprising toll-like receptor agonists and the use of such conjugates for the treatment of cancer. In some embodiments, the conjugates comprise anti-HER2 antibodies. In some embodiments, the conjugates are used in combination with a second therapeutic agent.
