ゲフィチニブ 化学特性,用途語,生産方法
外観
白色～わずかにうすい褐色、結晶性粉末～粉末
溶解性
ジメチルスルホキシド溶状：試験適合ジメチルスルホキシドに溶け、アセトン、エタノール及び水に難溶である。
解説
ゲフィチニブ，抗悪性腫瘍(しゅよう)薬。製品名は「イレッサ」で、イギリスのアストラゼネカ社により合成、開発された分子標的薬。悪性腫瘍細胞の増殖、維持に関与している上皮成長因子受容体（EGFR）チロシンキナーゼを阻害する。非小細胞肺癌(がん)に劇的に効果が認められたことから2002年（平成14）7月世界にさきがけて日本で承認された。適応は手術不能または再発非小細胞肺癌。白色の粉末で、製剤は錠剤（250ミリグラム）。1日1回250ミリグラムを経口投与する。比較的ゆるやかに吸収され、食事の影響は受けない。
用途
EGFR チロシンキナーゼ阻害
剤です。特に変異型 EGFR に対してより低濃
度で阻害活性を示します。
効能
抗悪性腫瘍薬, 受容体チロシンキナーゼ阻害薬
副作用
副作用は、発疹、下痢(げり)、掻痒(そうよう)症、皮膚乾燥など。重大な副作用として、急性肺障害、間質性肺炎、重度の下痢、脱水、中毒性表皮壊死(えし)融解症、肝炎、血尿、急性膵炎(すいえん)がある。
商品名
イレッサ (アストラゼネカ); ゲフィチニブ (ダイト); ゲフィチニブ (日医工); ゲフィチニブ (日本ジェネリック); ゲフィチニブ (日本化薬); ゲフィチニブ (沢井製薬); ゲフィチニブ (高田製薬)
説明
Gefitinib was introduced in Japan as a daily oral monotherapy for the treatment of
inoperable or recurrent non-small cell lung cancers (NSCLC). This anilinoquinazoline
derivative can be synthesized in 6 steps starting from 6,7-dimethoxyquinazolin-4(3H)-one
by successive monodemethylationlacetylation of the 6-hydroxy-group followed by
chlorination and reaction with 3-chloro-4-fluoroaniline, finally deacetylation and alkylation
with 3-(4-morpholinyl)propylbromide complete the synthesis. Gefitinib reversibly inhibits
the activity of the epidermal growth factor receptor tyrosine kinase (EGRF TK). This
inhibits autophosphorylation of EGRF and blocks the cascade of intracellular events which
have been implicated in the proliferation, survival and metastasis of cancer cells. Gefitinib
diplays good selectivity for the EGRF TK relative to other growth factors in human
umbilical endothelial cells. It is similarly selective relative to other kinases, for example cerB2.
Data from two large phase II studies in patients with pretreated NSCLC have shown
that gefitinib induces a response rate approaching 20% in patients receiving the agent as a second line therapy and approximately 10% in those pretreated with more lines of
chemotherapy. Gefitinib has good bioavailability and is metabolized in the liver via the
cytochrome P450 3A4 enzyme system with a mean elimination half life of 28 h. Gefitinib
has been generally well tolerated in cancer patients with predominant side effects being
acne-like skin-rash, diarrhea, nausea, vomiting and mild to moderate myelosuppression.
.
化学的特性
Light-Yellow Crystalline Powder
使用
Gefitinib is an antineoplastic.
適応症
The EGFR or ErbB1 inhibitor gefitinib (Iressa(R), AstraZeneca) was originally approved by the US FDA in 2003 under accelerated regulations for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after progression on docetaxel- and platinum-based chemotherapy. AstraZeneca voluntarily withdrew gefitinib from the market in 2005, owing to failed verification of clinical benefit during post-approval studies. In July 2015, FDA reinstated the approval of gefitinib for a different group of patients (i.e., NSCLC patients with EGFR mutations).
Other approved kinase inhibitors targeting the ErbB family, which includes ErbB1/EGFR, ErbB2/human epidermal growth factor receptor 2 (Her2), ErbB3/ Her3, and ErbB4/Her4, are erlotinib (Tarceva(R), OSI Pharm.), lapatinib (Tykerb(R), GlaxoSmithKline), vandetanib (Caprelsa(R), AstraZeneca), afatinib (Gilotrif(R), Boehringer Ingelheim) , and osimertinib (Tagrisso(R), AstraZeneca). All approved EGFR family inhibitors share a common quinazoline scaffold with the exception of osimertinib, which has a pyrimidinylphenylamine scaffold that resembles that of imatinib and nilotinib. Gefitinib and vandetanib adopt the type I binding mode with “DFG-in” and αC-helix “in” conformation, while erlotinib and lapatinib bind to“DFG-in”with the αC-helix adopting an “out” conformation. Afatinib and osimertinib are covalent inhibitors with an electrophilic enone moiety.
一般的な説明
Geftinib is available as 250-mg tablets for oral administrationin the treatment of NSCLC for those patients who have failedto respond to platinum-based therapies and docetaxel and hasalso been used against squamous cell cancers of the head andneck. The agent is an inhibitor of the TK of EGF-R and possiblyother TKs as well. Gefitinib is both a substrate and inhibitorof Pgp and BCRP. The agent is absorbed slowly afterbeing administered orally with 60% bioavailability.Metabolism occurs in the liver and is mediated primarily byCYP3A4 to give eight identified metabolites resulting fromdefluorination of the phenyl ring, oxidative-O-demethylation,and multiple products arising as a result of oxidation of themorpholine ring. The O-demethylated product represents thepredominate metabolite and is 14-fold less active comparedwith the parent. The parent and metabolites are eliminated inthe feces with a terminal elimination half-life of 48 hours.The drug appears to be well tolerated with the most commonlyreported side effects being rash and diarrhea. It mayalso cause elevations in blood pressure especially in those patientswith preexisting hypertension, elevation of transaminaselevels, and mild nausea and mucositits.
生物活性
Orally active, selective inhibitor of EGFR tyrosine kinase (IC 50 = 23-79 nM). Shows minimal activity against ErbB2, KDR, c-flt, PKC, MEK and ERK-2. Blocks EGFR autophosphorylation and inhibits tumor growth in mice bearing a range of human xenografts.
ゲフィチニブ 上流と下流の製品情報
原材料
準備製品