ALK-克唑替尼

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赛可瑞克唑替尼胶囊服用方法和饮食禁忌

辉瑞赛可瑞克唑替尼（Xalkori）服用方法和饮食禁忌本文由印康源海外医疗整理提供，辉瑞研发的赛可瑞克唑替尼胶囊是Met/ALK/ROS的ATP竞争性的多靶点蛋白激酶抑制剂，主要用于治疗间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移性非小细胞肺癌（NSCLC）。

辉瑞面向印度市场，开发了品牌名称为Crizalk的印度版克唑替尼，另外还有印度本地品牌的克唑替尼（微信：yinkangyuan88）。

不论是哪个版本的克唑替尼，在开始治疗之前和服用过程中都有一些注意事项。

在开始治疗之前，医生可能会进行测试，以确保克唑替尼是您的肺癌类型的最佳治疗。

服用方法剂量和时间需医生处方。

不要加大或者减少药量或超过推荐的时间。

克唑替尼的推荐剂量为250mg，每天服用两次可以带食物或者不带食物服用不要粉碎，咀嚼，溶解或打开克唑替尼胶囊，整个吞下为了确保这种药物对病情有帮助，而且不会造成有害影响，血细胞和肝功能可能需要经常检测。

心脏功能可能需要使用心电图（ECG或EKG）进行测试。

根据这些测试的结果，癌症治疗可能会延迟未经医生允许，不要停止服用药物在室温下储存，远离湿气和热量，不用时请将瓶子盖紧。

如果忘记服用克唑替尼，如果记起，尽快服用，但是如果距离下次用药已经不足6小时，那么忽略掉这一次用药，按照正常药量和用药时间服药。

尽量避免在治疗期间进食葡萄柚和西柚汁。

有些药物可能会与克唑替尼产生相互作用。

华法林（Coumadin，Jantoven）等血液稀释剂环孢素（Gengraf，Neoral，Sandimmune），西罗莫司（Rapamune）或他克莫司（Prograf）地塞米松（Cortastat，Dexasone，Solurex，DexPak）地高辛（洋地黄，Lanoxin，Lanoxicaps）异烟肼（用于治疗结核病）尼卡地平（Cardene）匹莫齐特（Orap）圣约翰草茶碱（Elixophyllin，Theo-24，Theochron，Uniphyl）红霉素（E.E.S.，EryPed，Ery-Tab，Erythrocin，Pediazole），利福布丁（Mycobutin），利福平（Rifadin，Rifater，Rifamate），利福喷汀（Priftin）或泰利霉素（Ketek）去甲丙咪嗪（Norpramin），多塞平（Sinequan，Silenor），艾司西酞普兰（Lexapro），米氮平（Remeron），奈法唑酮，舍曲林（Zoloft），曲唑酮（Desyrel，Oleptro），三甲吡啶（Surmontil）或文拉法辛（Effexor）如伊曲康唑（Sporanox），酮康唑（Nizoral），咪康唑（Oravig）或伏立康唑（Vfend）等抗真菌药物司可巴比妥（Seconal），戊巴比妥（Nembutal）或苯巴比妥（Solfoton）等巴比妥类麦角胺（Ergomar，Cafergot）或二氢麦角胺（D.H.E.45，Migranal鼻喷雾剂）普鲁卡因胺（Procan，Pronestyl）或奎尼丁（Quin-G）等心脏节律药物阿扎那韦（Reyataz），地拉呋啶（Delavirdine），依非韦伦（Efavirenz），依地韦林（Etivirenz），依地韦林（Etravirine），茚地那韦（Crixivan），奈非那韦（Viracept），奈韦拉平（Viramune），利托那韦（Norvir，Kaletra）或沙奎那韦（Invirase）非氨酯（Felbatol），奥卡西平（Trileptal），苯妥英（Dilantin），扑米酮（Mysoline）或丙戊酸（Depakene，Stavzor）以上未列出所有可能与克唑替尼产生相互作用的药物，还有许多其他药物可以与克唑替尼相互作用。

克唑替尼原理

克唑替尼原理
克唑替尼是一种针对ALK阳性的非小细胞肺癌（ NSCLC）的靶向治疗药物。

它的原理是通过抑制ALK融合基因所编码的酪氨酸激酶的活性，从而阻断肿瘤细胞的增殖和侵袭。

克唑替尼在2011年获得美国FDA的批准，用于治疗晚期或转移性的ALK阳性NSCLC，是第一个针对ALK的靶向药物。

多项临床试验表明，克唑替尼相比传统的化疗，能够显著提高ALK阳性NSCLC 患者的客观缓解率、无进展生存期和总生存期，同时具有较好的耐受性和安全性。

然而，克唑替尼并非万能的，它也存在一些不良反应和局限性。

最重要的问题就是耐药，即患者在使用克唑替尼一段时间后，肿瘤细胞会发生一些变化，使得克唑替尼失去了原有的抑制作用，导致疾病的恶化或复发。

目前已知的耐药机制主要有以下几种：
-（ALK二级突变：指ALK融合基因的酪氨酸激酶结构域内发生的导致氨基酸替换的点突变，使得ALK融合蛋白对克唑替尼的亲和力降低或失去，从而降低克唑替尼的抑制效果。

-（ALK基因扩增：指ALK融合基因在染色体上的拷贝数增加，导致ALK融合蛋白的表达水平升高，从而抵消克唑替尼的抑制作用。

-（躲避信号通路的激活：指肿瘤细胞通过激活其他与ALK信号
通路平行或下游的信号通路，如EGFR、KRAS、PI3K/AKT、MAPK等，来维持细胞的增殖和存活，从而规避克唑替尼的抑制作用。

-（肿瘤微环境的改变：指肿瘤细胞周围的血管、基质、免疫细胞等发生的变化，影响克唑替尼的药物输送、代谢和效应，从而降低克唑替尼的治疗效果。

克唑替尼说明书

_______________________________________________________________________________________________________________________________________ _______________________________________________________________________________________________________________________________________ HIGHLIGHTS OF PRESCRIBING INFORMATION •QTInterval Prolongation: Occurred in 2.7% of patients. Monitor with These highlights do not include all the information needed to use electrocardiograms and electrolytes in patients who have a history of orXALKORI ®safely and effectively. See full prescribing information for predisposition for QTc prolongation, or who are taking medications that XALKORI. prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.3) XALKORI ® (crizotinib) Capsules, oral • Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and Initial U.S. Approval: 2011blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.4) ----------------------------INDICATIONS AND USAGE---------------------------•Embryofetal Toxicity: XALKORI can cause fetal harm when XALKORI is a kinase inhibitor indicated for the treatment of patients with administered to a pregnant woman. (5.5, 8.1) metastatic non-small cell lung cancer (NSCLC)whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. (1)------------------------------ADVERSE REACTIONS-------------------------------The most common adverse reactions (≥25%) are vision disorders, nausea, ----------------------DOSAGE AND ADMINISTRATION-----------------------diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. •Recommended dose: 250 mg orally, twice daily (2.2) (6) • Renal Impairment: 250 mg orally,once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiringTo report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. atdialysis. (2.2)1-800-438-1985 or FDA at 1-800-FDA-1088 or /medwatch . •Dosing interruption and/or dose reductions may be required based on adverse drug reactions. (2.3)------------------------------DRUG INTERACTIONS-------------------------------• CYP3AInhibitors: Avoid concurrent use of XALKORI with strong ---------------------DOSAGE FORMS AND STRENGTHS----------------------CYP3A inhibitors. (7.1)• Capsules: 250 mg and 200 mg (3) • CYP3AInducers: Avoid concurrent use of XALKORI with strong CYP3A inducers. (7.2)-------------------------------CONTRAINDICATIONS------------------------------• CYP3A Substrates: Avoid concurrentuse of XALKORI with CYP3A • None (4) substrates with narrow therapeutic indices. (7.3)See 17 forPATIENT COUNSELING INFORMATION and FDA------------------------WARNINGS AND PRECAUTIONS------------------------• Hepatotoxicity: Fatal hepatotoxicity occurred in 0.2% of patients. approved patient labeling.Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.1) Revised: 03/2015• Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2% of patients. Permanently discontinue in patients with ILD/pneumonitis. (5.2)FULL PRESCRIBING INFORMATION: CONTENTS*8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 1 INDICATIONS AND USAGE8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION8.5 Geriatric Use 2.1Patient Selection 8.6 Hepatic Impairment 2.2Recommended Dosing 8.7 Renal Impairment 2.3Dose Modification 10 OVERDOSAGE 3DOSAGE FORMS AND STRENGTHS 11 DESCRIPTION 4CONTRAINDICATIONS 12 CLINICAL PHARMACOLOGY 5 WARNINGS AND PRECAUTIONS12.1 Mechanism of Action 5.1Hepatotoxicity 12.2 Pharmacodynamics 5.2Interstitial Lung Disease (Pneumonitis) 12.3 Pharmacokinetics 5.3QT Interval Prolongation 5.4Bradycardia 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.5 Embryofetal Toxicity 14 CLINICAL STUDIES 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS 7.1 Drugs That May Increase Crizotinib Plasma Concentrations * Sections or subsections omitted from the Full Prescribing Information are 7.2 Drugs That May Decrease Crizotinib Plasma Concentrations not listed. 7.3 Drugs Whose Plasma Concentrations May Be Altered By CrizotinibFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEXALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.2 DOSAGE AND ADMINISTRATION2.1 Patient SelectionSelect patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.2.2 Recommended DosingThe recommended dose of XALKORI is 250 mg orally, twice daily until disease progression or no longer tolerated by the patient. The recommended dose of XALKORI in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time.2.3 Dose ModificationReduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: •First dose reduction: XALKORI 200 mg taken orally twice daily•Second dose reduction: XALKORI 250 mg taken orally once daily•Permanently discontinue if unable to tolerate XALKORI 250 mg taken once dailyDose reduction guidelines are provided in Tables 1 and 2.Table 1. XALKORI Dose Modification – Hematologic Toxicities aCTCAE Grade XALKORI DosingGrade 3 Withhold until recovery to Grade 2 or less, then resume at the same dose scheduleGrade 4 Withhold until recovery to Grade 2 or less, then resume at next lower dosea Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).Table 2. XALKORI Dose Modification – Non-Hematologic ToxicitiesCriteria XALKORI DosingAlanine aminotransferase (ALT) or aspartate Withhold until recovery to baseline or less than or equal to 3 times aminotransferase (AST) elevation greater ULN, then resume at reduced dosethan 5 times upper limit of normal (ULN)with total bilirubin less than or equal to1.5 times ULNALT or AST elevation greater than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) Permanently discontinueAny Grade drug-related interstitial lung disease/pneumonitis Permanently discontinueQTc greater than 500 ms on at least 2 separate ECGs Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at reduced doseQTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinueBradycardia a (symptomatic, may be severe and medically significant, medical intervention indicated) Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or aboveEvaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medicationsIf contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or aboveIf no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or aboveBradycardia a,b (life-threatening consequences, urgent intervention indicated) Permanently discontinue if no contributing concomitant medication is identifiedIf contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoringab Permanently discontinue for recurrence.Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs.3 DOSAGE FORMS AND STRENGTHS250 mg capsulesHard gelatin capsule, size 0, pink opaque cap and body, with “Pfizer” on the cap and “CRZ 250” on the body.200 mg capsulesHard gelatin capsule, size 1, white opaque body and pink opaque cap, with “Pfizer” on the cap and “CRZ 200” on the body.4 CONTRAINDICATIONSNone5 WARNINGS AND PRECAUTIONS5.1 HepatotoxicityDrug-induced hepatotoxicity with fatal outcome occurred in 2 (0.2%) of the 1225 patients treated with XALKORI across three main clinical trials. Concurrent elevations in alanine aminotransferase (ALT) greater than three times the upper limit of normal and total bilirubin greater than two times the upper limit of normal, with normal alkaline phosphatase, occurred in 7 patients (0.6%). Additionally, elevations in ALT greater than five times the upper limit of normal occurred in 109 patients (9.2%). Eight patients (0.7%) required permanent discontinuation due to elevated transaminases. These laboratory findings were generally reversible upon dosing interruption. Transaminase elevations generally occurred within the first 2 months of treatment.Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6)].5.2 Interstitial Lung Disease (Pneumonitis)Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1225), 31 XALKORI-treated patients (2.5%) had any grade ILD,11 patients (0.9%) had Grade 3 or 4, and 6 patients (0.5%) had fatal cases. These cases generally occurred within 2 months after the initiation of treatment.Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-relatedILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)].5.3 QT Interval ProlongationQTc prolongation can occur in patients treated with XALKORI. Across clinical trials (n=1225), QTc prolongation (all grades) was observed in 34 (2.7%) patients and QTc greater than 500 ms on at least 2 separate ECGs occurred in 17 (1.4%) patients.Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia orsigns/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)].5.4 BradycardiaSymptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia with a heart rate less than 50 beats per minute occurred in 11% of 1174 patients treated with XALKORI. In Study 1, Grade 3 syncope occurred in 2.9% of XALKORI-treated patients and in none of the chemotherapy-treated patients.Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)].5.5 Embryofetal ToxicityXALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily. There are no adequate and well-controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONSThe following adverse reactions are discussed in greater detail in other sections of the labeling: •Hepatotoxicity [see Warnings and Precautions (5.1)]•Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]•QT Interval Prolongation [see Warnings and Precautions (5.3)]•Bradycardia [see Warnings and Precautions (5.4)]6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Safety evaluation of XALKORI is based on more than 1200 patients with ALK-positive metastatic NSCLC who received XALKORI as monotherapy at a starting oral dose of 250 mg twice daily continuously.The most common adverse reactions (≥25%) of XALKORI are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.ALK-positive metastatic NSCLC-Study 1The data in Table 3 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 1). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 84% of patients in the XALKORI arm and 87% of patients in the chemotherapy arm were younger than 65 years. A total of 57% of patients on XALKORI and 55% of chemotherapy patients were female. Forty-six percent (46%) of XALKORI-treated and 45% of chemotherapy-treated patients were from Asia.Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and interstitial lung disease (ILD; 2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 1 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).Discontinuation of therapy in XALKORI-treated patients for adverse reactions was 17.0%. The most frequent adverse reactions that led to discontinuation in XALKORI-treated patients were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 3 and 4 summarize common Adverse Reactions and Laboratory Abnormalities in XALKORI-treated patients.Table 3. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 1 Adverse Reaction XALKORI (N=172) Chemotherapy (Pemetrexed or Docetaxel) (N=171) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Nervous System Disorder Dizziness aDysgeusia Syncope 22 26 3 1 0 3 8 9 0 0 0 0 Eye Disorders Vision disorder b60 0 9 0 Cardiac Disorders Electrocardiogram QT prolonged Bradycardia c5 5 3 0 0 0 0 0 Investigations Weight decreased 10 1 4 0 Gastrointestinal Disorders Vomiting Nausea Diarrhea Constipation Dyspepsia 47 55 60 42 8 1 1 0 2 0 18 37 19 23 3 0 1 1 0 0 Infections and Infestations Upper respiratory infection d 26 0 13 1 Respiratory, Thoracic and Mediastinal Disorders Pulmonary embolism e 6 5 2 2 General Disorders and Administration Site Conditions Edemaf 31 0 16 0 Includes cases reported within the clustered terms:aDizziness (Balance disorder, Dizziness, Dizziness postural) bVision Disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters) cBradycardia (Bradycardia, Sinus bradycardia) dUpper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection) ePulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism) fEdema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Edema peripheral, Periorbital edema) Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).Table 4. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of≥4% in XALKORI-Treated Patients Laboratory Abnormality CrizotinibAny Grade Grade 3/4 ChemotherapyAny Grade Grade 3/4HematologyNeutropeniaLymphopenia 49%51%12%9%28%60%12%25%ChemistryALT elevationAST elevationHypokalemiaHypophosphatemia 76%61%18%28%17%9%4%5%38%33%10%25%4%0%1%6%ALK-positive metastatic NSCLC-Study 2The safety analysis population in Study 2 included 934 patients with ALK-positive metastatic NSCLC who received XALKORI in a clinical trial. The median duration of treatment was 23 weeks. Dosing interruptions and reductions due to treatment-related adverse events occurred in 23% and 12% of patients, respectively. The rate of treatment-related adverse events resulting in permanent discontinuation was 5%. The most common adverse reactions (≥25%) included vision disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), constipation (38%), and fatigue (26%).Description of selected adverse drug reactionsVision disordersVision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 691 (56%) patients across clinical trials (n=1225). The majority (99%) of these patients had Grade 1 or 2 visual adverse reactions. Across clinical studies, one patient had a treatment-related grade 3 vision abnormality.Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Study 1 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorders generally started within the first week of drug administration. The majority of patients on the XALKORI arm in Study 1 (> 50%) reported visual disturbances; these visual disturbances occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in a patient questionnaire.NeuropathyNeuropathy, most commonly sensory in nature, occurred in 235 (19%) of 1225 patients. Most events (95%) were Grade 1 or Grade 2 in severity.Renal CystsRenal cysts occurred in 7 (4%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 1. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.7 DRUG INTERACTIONS7.1 Drugs That May Increase Crizotinib Plasma ConcentrationsCoadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inhibitors, including but not limited toatazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors.7.2 Drugs That May Decrease Crizotinib Plasma ConcentrationsCoadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort.7.3 Drugs Whose Plasma Concentrations May Be Altered By CrizotinibCrizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category D [see Warnings and Precautions (5.5)]XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies of XALKORI in pregnant women. In nonclinical studies in rats, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the recommended clinical dose of 250 mg twice daily. Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥ 50 mg/kg/day (approximately 0.6 times the AUC at the recommended human dose) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the AUC at the recommended human dose) or in rabbits at doses of up to60 mg/kg/day (approximately 1.6 times the AUC at the recommended human dose), though fetal body weights were reduced at these doses.Advise women of childbearing potential to avoid becoming pregnant while receiving XALKORI. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for at least 90 days after completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.8.3 Nursing MothersIt is not known whether XALKORI is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from XALKORI, consider whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days(approximately 5.4 times the AUC in adult patients at the recommended human dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.8.5 Geriatric UseOf XALKORI treated patients in Study 1, 27 (16%) were 65 years or older, in Study 2, 152 (16%) were65 years or older, and in Study 3, 16 (13%) were 65 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.8.6 Hepatic ImpairmentXALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded patients with AST or ALT greater than 2.5 x ULN, or greater than 5 x ULN, if due to liver metastases. Patients with total bilirubin greater than 1.5 x ULN were also excluded. Therefore, use caution in patients with hepatic impairment [see Clinical Pharmacology (12.3)].8.7 Renal ImpairmentNo starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a population pharmacokinetic analysis.Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis [see Dosage and Administration (2.2) and ClinicalPharmacology (12.3)].10 OVERDOSAGEThere have been no known cases of XALKORI overdose. There is no antidote for XALKORI.11 DESCRIPTIONXALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib isC21 H22 C l2FN5O. The molecular weight is 450.34 Daltons. Crizotinib is described chemically as (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.。

口服克唑替尼胶囊致肝功能异常一例

-1268-Chinese Journal of New Clinical Medicine,December2020,Volume13,Number12口服克卩坐替尼胶囊致肝功能异常一例•病例报告-杨怡侠，杨宏昕作者单位：010000内蒙古自治区，呼和浩特市蒙医中医医院药剂科（杨怡侠）；010000呼和浩特，内蒙古自治区人民医院药剂处（杨宏昕）作者简介：杨怡侠（1969-），女，心理学硕士，副主任药师，研究方向：临床药学。

E-mWl：15853920@通讯作者：杨宏昕（1968-）,女,大学本科,学士学位，主任药师,研究方向：药事管理&E-mWl:ny1882@［关键词］克唑替尼；肝功能异常；用药分析；临床药师［中图分类号］R734.2［文章编号］1674-3806（2020）12-1268-03doi：10.3969/j.issn.1674-3806.2020.12.21肺癌是临床上最常见的恶性肿瘤之一,非小细胞肺癌（non-smal l cell lung cancer,NSCLC）属其中一种，具有较高的病死率，预后普遍较差。

大量数据表明，约75%的患者就诊时已处于中晚期，耽误了最佳的治疗时机［1］&近年来，肺癌的传统化疗未见突破性进展。

在21世纪初随着吉非替尼的上市，靶向治疗已成为NSCLC最重要的治疗手段之一'2（&克唑替尼是一种高度选择性的酪氨酸激酶受体抑制剂,可阻断酪氨酸激酶的活性,通过抑制细胞信号转导抑制肿瘤细胞的生长、增殖，并促进肿瘤细胞凋亡，达到抗癌的目的［3］&《NCCN临床实践指南:非小细胞肺癌》推荐克唑替尼用于间变淋巴瘤激酶（anaplastic lymphomv kinase,ALK）基因重排患者的一线治疗⑷&克唑替尼主要通过肝微粒体酶进行代谢，酶的代谢活性直接影响克唑替尼在体内的血药浓度&临床用药过程中会产生肝毒性，使患者血清中氨基转移酶严重升高,从而导致停药，影响患者正常治疗，可能导致疾病进展&1病例介绍患者，女,41岁，因患NSCLC,2019-08下旬开始口服克唑替尼胶囊（生产厂家:POzer Manufacturing Deutschland GmbH,Betoebsstat t a Freibury,批号：AW8335）250my,2次/d,服用后出现恶心呕吐不适，服药半月后减量为250my,1次/d,仍有恶心不适，服药1个月后全面复查病情稳定&2019-10-28门诊复查，化验肝功能提示天门冬氨酸转移酶354.30U/L,丙氨酸转移酶1225.00U/L,总胆红素40.20.mol/L,直接胆红素21.20.mol/L,立即停止服用克唑替尼胶囊并住院治疗&患者自发病以来精神睡眠可，饮食可，二便如常，体重无显著变化&入院后彩超显示肝多发囊肿、胆囊息肉、左肾囊肿&予注射用还原性谷胱甘肽1.8y,静脉点滴1次/d,注射用丁二磺酸腺苷蛋氨酸1000my,静脉点滴1次/d,同时口服双环醇片50my,3次/d,保肝治疗，监测肝功能变化&11月2日复查肝功能:天门冬氨酸转移酶21.00U/L,丙氨酸转移酶182.60U/L,总胆红素35.30.mol/L,直接胆红素16.80.mol/L,继续保肝治疗&11月6日再次复查肝功能:天门冬氨酸转移酶235.40U/L,丙氨酸转移酶593.90U/L,总胆红素35.30.mol/L,直接胆红素16.80.mol/L&患者丙氨酸转移酶较前下降，胆红素无明显变化，继续保肝治疗&11月8日患者要求出院回当地治疗,停用注射用还原性谷胱甘肽和注射用丁二磺酸腺苷蛋氨酸，嘱患者继续口服双环醇片，同时服用复方甘草酸苷片2片,3次/d,嘱患者继续规律治疗后监测肝功能变化情况，指标允许继续靶向治疗，不适随诊&2讨论患者2019-07-00化验肝功能正常&8月下旬开始使用克唑替尼胶囊单药治疗&患者于10月28日复查时自述近1个月食欲减退、厌油、恶心&查肝功能天门冬氨酸转移酶、丙氨酸转移酶、总胆红素、直接胆红素均显著升高，立即停止使用克唑替尼并住院治疗，治疗11d后丙氨酸转移酶较前显著下降& 2.1患者肝功能异常原因分析患者开始使用克唑替尼胶囊前，肝功能正常，且患者未服用其他药物进行治疗&患者使用克唑替尼胶囊治疗2个月内出现肝功能异常，与文献［5］报道克唑替尼肝毒性一般在服药的前2个月出现相符&克唑替尼胶囊最常见的不良反应（"25%）为视觉异常、恶心、腹泻、呕吐、便秘、水肿、转氨酶升高及疲乏&克唑替尼致死性肝毒性的发生率为0.2%，一般在服药的前2个月出现,因此建议使用克唑替尼胶囊的前2个月应每2周监中国临床新医学2020年12月第13卷第12期-1269-测1次肝功能[6]&综合评价,该患者的肝功能异常很可能与服用克唑替尼胶囊相关。

克唑替尼治疗EML4-ALK重排阳性患者的临床疗效

克唑替尼治疗EML4-ALK重排阳性患者的临床疗效吴璇;李建雄【摘要】Objective To evaluate the therapeutic effects of different therapeutic regimens for non-small-cell lung cancer (NSCLC) with or without EML4-ALK rearrangement. Methods Twenty-one ALK-positive and 50 ALK-negative NSCLC patients who received voluntarily EML4-ALK testing and 75 NSCLC patients without AL testing were enrolled in this study. The 3 groups of patients received different treatments, and the therapeutic effects, progression-free survival (PFS), and treatment-related adverse events were analyzed. Result Crizotinib treatment obviously prolonged the PFS in EML4-ALK-positive patients with an objective response rate (OOR) of 61.9%and a median response duration of 16 months, which were significantly better than those in with ALK-negative patients and patients without ALK testing who received different second-line therapies. Conclusion Crizotinib is superior to platinum- based chemotherapy in NSCLC patients with ALK rearrangement. ALK rearrangement id not a modifier of the effect of chemotherapy regimens in NSCLC patients.%目的：探讨EML4-ALK融合基因阳性与阴性非小细胞肺癌患者在应用不同治疗方案后的临床疗效。

克唑替尼中文说明书

克唑替尼说明书(中文)【药物名】Xalkori 【商品名】Crizotinib (克唑替尼) 【美国上市时间】o ROS-1阳性非小细胞肺癌；o FDA 批准的检测方法确定的间变性淋巴瘤激酶( ALK)阳性的局部晚期患者；上市时间：2011 年【类别】酪氨酸酶抑制剂【靶点】ALK【分子结构】分子式：C21H22C l2 FN5O化学名：(R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine 结构式为：分子量为：450.34 KDa【生产公司】Pfizer 辉瑞公司【购买地】美国【剂型和规格】口服胶囊，剂量为250mg和200mg。

250mg胶囊：硬明胶胶囊，大小0，粉色不透明帽和体，在帽上有“ Pfizer ”和体上“ CRZ 250” ，60胶囊瓶：NDC 0069-8140-20。

200mg胶囊：硬明胶胶囊，大小1，白色不透明体和粉色不透明帽，帽上有“ Pfizer 和体上“ CRZ 200”，60胶囊瓶：NDC 0069-8141-20。

【本质】克唑替尼胶囊硬壳含250 mg 或200 mg 的克唑替尼胶体二氧化硅，微晶纤维素，无水磷酸氢钙，羟基乙酸淀粉钠，硬脂酸镁和硬胶囊胶囊壳为无活性成分。

粉红色不透明胶囊壳组分含明胶，二氧化钛，和氧化铁红。

白色不透明胶囊壳组分含明胶和二氧化钛。

印刷油墨含有虫胶，丙二醇，强氨水溶液，氢氧化钾，和黑色氧化铁。

【作用机理】克唑替尼是酪氨酸激酶受体包括ALK，肝细胞生长因子受体（HGFR, c-Met），ROS1（c-ros），和酪氨酸激酶（RON）的一种抑制剂。

易位可影响ALK基因导致致癌融合蛋白的表达。

ALK融合蛋白的形成导致激活和基因表达和增加细胞增殖有贡献信号的调节异常而生存肿瘤表达这些蛋白。

克唑替尼就是通过阻断对肿瘤细胞生长与存活起关键作用的多种细胞通路，导致肿瘤的稳定或消退。

克唑替尼胶囊(赛可瑞)说明书

克唑替尼胶囊（赛可瑞）【规格】250mg、200mg【适应症】可用于经SFDA批准的检测方法确定的间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移性非小细胞肺癌（NSCLC）患者的治疗。

【禁忌症】对本品有严重超敏反应者禁用。

【用法用量】推荐剂量为250mg口服，每日两次。

胶囊应整粒吞服。

克唑替尼胶囊与食物同服或不同服均可。

若漏服一剂克唑替尼胶囊，则补服漏服剂量的药物，除非距下次服药时间短于6小时。

【不良反应】1、视觉异常：包括视觉损害、闪光感、视物模糊、玻璃体浮游物、畏光和复视。

上述不良事件通常在给药后两周内开始发生。

若患者出现闪光感或首次出现玻璃体浮游物或加重时，应考虑进行眼科检查。

2、心脏异常：心动过缓，也观察到QTc延长。

3、肾脏损伤：发生复杂性肾囊肿。

4、实验室检查异常：中性粒细胞减少、血小板减少和淋巴细胞减少。

5、消化道反应：消化不良、吞咽困难、上腹部不适，疼痛，烧灼感、食管炎、食管梗阻，溃疡、胃食管反流、吞咽疼痛和反流性食管炎。

6、全身异常：水肿，局部水肿和外周水肿。

7、神经系统：感觉迟钝、感觉过敏、感觉减退、神经痛、感觉异常、周围神经病变、外周运动神经病变和外周感觉神经病变。

【注意事项】1.根据不同患者安全性与耐受性可中断治疗或减少剂量。

如需减少剂量，则降低克唑替尼胶囊至200mg口服，每日两次。

若需要进一步减少剂量，则根据患者安全性和耐受性将剂量调整为250mg口服，每日一次。

2.育龄妇女在服用克唑替尼胶囊进行治疗时应尽量避免怀孕。

3.定期检查肝功能。

包括ALT和总胆红素，每月至少应检测一次，并且根据临床状况对氨基转移酶水平升高的患者更频繁地进行重复检测肝氨基转移酶、碱性磷酸酶或总胆红素升高水平。

在出现不良反应时进行减量或中断给药。

4.观测到QTc间期延长。

先天性长QT综合征患者应避免服用克唑替尼胶囊。

对于充血性心力衰竭、缓慢性心律失常和电解质异常患者，以及正在服用已知可致QT间期延长药物的患者，使用本品治疗时应定期监测其心电图与电解质。

克唑替尼的全面解析

克唑替尼的主要作用
克唑替尼的抗肿瘤作用
克唑替尼是一种有效的抗癌药物，能够抑制肿瘤细胞的生长和扩散。
克唑替尼的靶向治疗机制
克唑替尼通过靶向特定的分子靶点，阻断癌细胞的信号传导，从而抑制其生长和繁殖。
克唑替尼的临床应用范围
克唑替尼主要用于治疗某些类型的肺癌、甲状腺癌和其他恶性肿瘤，具有较好的疗效和耐受性。
克唑替尼的疗效评估结果
根据临床试验数据，克唑替尼在治疗ALK阳性非小细胞肺癌方面表现出良好的疗效。
克唑替尼的研究进展
克唑替尼的新药研发动态
克唑替尼的研发进展
该药物已进入临床试验阶段，显示出良好的疗效和安全性。
克唑替尼的适应症范围
主要用于治疗非小细胞肺癌，对其他癌症也有一定的治疗效果。
克唑替尼的市场前景
克唑替尼对患者社交活动的影响
克唑替尼可能使患者情绪低落，影响其参与社交活动的积极性。
克唑替尼对家庭经济的影响
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克唑替尼的药品价格
克唑替尼作为治疗肺癌的靶向药物，其价格较高，给患者家庭经济带来压力。
克唑替尼的医保报销情况
虽然克唑替尼已纳入医保目录，但部分地区报销比例较低，仍需自费部分费用。
克唑替尼的经济负担对家庭的影响
长期使用克唑替尼可能导致家庭经济负担加重，影响生活质量和家庭成员的福利。
克唑替尼对社会医疗资源的影响
克唑替尼的高昂价格
克唑替尼的价格昂贵，给患者带来了经济负担，增加了社会医疗资源的压力。
克唑替尼的疗效与副作用
克唑替尼虽然对某些癌症有显著疗效，但也存在一些副作用，需要额外的医疗资源进行管理和处理。
克唑替尼对特定癌症的影响
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【药物发现】抗癌药阿来替尼的诞生

【药物发现】抗癌药阿来替尼的诞生前面给大家介绍了第一代ALK 靶向药克唑替尼的研发过程（点此链接查看原文），提到了大部分患者使用克唑替尼在1年左右会发生ALK耐药性突变，部分患者甚至会发生癌细胞脑转移。

而克唑替尼很难穿过血脑屏障，其在脑脊液和游离血浆中的浓度比值仅为0.03。

因此研发对ALK突变有效且能穿过血脑屏障的二代ALK靶向药是非常重要的。

幸运的是，目前已有多款二代ALK靶向药被FDA批准上市了，如诺华的赛瑞替尼 (ceritinib)，罗氏的阿来替尼 (alectinib)和武田制药的布加替尼(brigatinib)等。

根据美国国家综合癌症网络（National Comprehensive Cancer Network, NCCN）发布的2021v1版的非小细胞肺癌（NSCLC）的临床实践指南，阿来替尼是ALK阳性非小细胞肺癌(NSCLC)中优先级最高的一线治疗药物（图1）。

今天，就由笔者给读者们回顾抗癌药阿来替尼的研发过程，深入了解为何阿来替尼是目前ALK阳性NSCLC患者首选的靶向药。

图1. NCCN发布的ALK阳性NSCLC患者的一线治疗指南。

——先导化合物的发现——日本的中外制药株式会社（Chugai Pharmaceutical Co.，已被罗氏收购)的研究人员从公司内部的分子库筛出了对ALK有弱抑制活性（IC50 = 1.3 μM）的四环化合物7 (图2)，该骨架是以往没有被发现过的；而且不同于克唑替尼对c-MET和ALK的活性都很好，7对c-MET的抑制活性很差（IC50 > 50 μM），说明7有可能是潜在的高选择性ALK抑制剂。

接下来就是常规的构效关系研究。

研究者首先分析了3号位取代基对ALK抑制活性的影响，结果发现3-取代基的烷基链长度和电子性质对于ALK抑制活性都是不重要的。

接下来，研究人员将骨架从苯并呋喃改为吲哚（可以作为氢键给体），发现 3-溴-四环吲哚取代的化合物14的活性（IC50 = 0.10 μM）比相应的11（IC50 = 0.77 μM）提高了7倍。

癌症的个体化治疗—克唑替尼的研发与应用

ＰＨＡ－６６５７５２与非磷酸化ＭＥＴ激酶域的共晶结构设计而成的。２一氨基一３一苄氧基吡啶系列化合物
可与非活性ＭＥＴ蛋白发生更有效的相互作用，并稳定其在非活化自抑制构象中，从而取得高的
细胞活性。通过对先导化合物系列进行优化，得到临床候选药物克唑替尼（ＰＦ－０２３４１０６６）。各
４５
中国药理通讯２０１３年第三十卷第二期
８月２６日快速通道批准了克唑替尼在ＡＬＫ阳性晚期肺癌患者中的使用。同时，克唑替尼在临床
试验中显示了多种与其靶点紧密相关的抗 ห้องสมุดไป่ตู้瘤活性，包括ＡＬＫ阳性的间变性大细胞淋巴瘤；炎性肌纤维母细胞性肿瘤；神经母细胞瘤患者；ＲＯＳ阳性的非小细胞肺癌患者；以及存在ＭＥＴ
而引起严重的毒副作用和降低人的免疫能力。随着对肿瘤细胞生物学的深入研究，正常细胞与
肿瘤细胞复杂信号通路的差异正在逐渐地被了解和揭示。阻断肿瘤细胞特异的信号通路从而达
到攻击肿瘤细胞的高选择性，低毒性的分子靶向治疗（ｍｏｌｅｃｕｌａｒｔａｒｇｅｔｔｈｅｒａｐｙ）正在受到越来越多的关注。１９９７年选择性作用于人类表皮生长因子受体２（Ｈｅｒ２）的曲妥珠单抗（ｔｒａｓｔｕｚｕｍａｂ）获批用于Ｈｅｒ２４－乳腺癌病人，以及２００１年Ａｂｌ蛋白激酶抑制剂伊马替尼获批用
炎症诱发肿瘤的机制探索

克唑替尼说明书,赛可瑞(克唑替尼)的使用方法和剂量调整说明

克唑替尼说明书，赛可瑞（克唑替尼）的使用方法和剂量调整说明克唑替尼是一种间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI），主要用于经国家食物药物监督局（SFDA）批准的检测方法确定的ALK阳性突变导致的局部或转移性非小细胞肺癌（NSCLC的治疗）。

克唑替尼在中国上市后，以中文名赛可瑞面向群众。

上市后的价格为53000元/盒，在2018年克唑替尼被纳入医保，报销后克唑替尼的价格为15000/盒，并且对于贫困患者可申请赠药补助，一般需自费服用国产克唑替尼6盒左右，也是相当不便宜，当然更多的人青睐海外的仿制药，例如比较常见的印度克唑替尼，在效果上与国内进口克唑替尼没什么差别，并且在价格上只有正版克唑替尼的一半，详情咨询qxy338，下面由倾杏医家整理出的可瑞（克唑替尼）中文说明书。

【用法用量】克唑替尼的推荐剂量为250mg/次,每日两次，需整理吞服，可在用餐时或餐后服用，若漏服一次需补服，并确保下次服用时间为6H之后。

【不良反应及处理方式】1、视觉异常：在服用克唑替尼两周后会明显感觉到实力减弱，眼部不适等症状，一般这种反应不需要特别干预，应避免夜间行车，情况严重时应询求医生帮助；2、食欲不振并伴随呕吐：在服用克唑替尼时，应注意少食多餐，食欲不振时吃一些清淡易消化的食物，可在餐时或餐后服用克唑替尼减轻呕吐症状；3、腹泻：一般出现这种情况可服用蒙脱石散缓解，情况严重时应口服补盐液，避免体内脱水等反应；4、便秘：主要通过饮食调节，患者在服药期间，应多吃易消化的食物，可在餐后食用富含维生素的水果有助于消化；5、肝功能异常：出现在这种症状应及时与医生反应，在医生的推荐下服用一些降酶的药物；6、间质性肺病；患者在服药期间，如有出现胸闷，发烧，缺氧等症状应及时就医治疗。

【剂量调整说明】在服用克唑替尼时，应根据不同患者对副作用的耐受性可以适量减少剂量或停止用药。

还有一些需要降低剂量的症状例如中性粒细胞减少，心脏毒性，肝功能损伤，间质性肺病等，患者应先降低剂量至200mg/次，每日两次，若仍不能耐受，可降低至250mg/次，每日一次。

克唑替尼中文说明书

250mg胶囊：硬明胶胶囊，大小0，粉色不透明帽和体，在帽上有“ Pfizer ”和体上“ CRZ 250” ，60胶囊瓶：NDC 0069-8140-20。

200mg胶囊：硬明胶胶囊，大小1，白色不透明体和粉色不透明帽，帽上有“ Pfizer 和体上“ CRZ 200”，60胶囊瓶：NDC 0069-8141-20。

粉红色不透明胶囊壳组分含明胶，二氧化钛，和氧化铁红。

白色不透明胶囊壳组分含明胶和二氧化钛。

印刷油墨含有虫胶，丙二醇，强氨水溶液，氢氧化钾，和黑色氧化铁。

【作用机理】克唑替尼是酪氨酸激酶受体包括ALK，肝细胞生长因子受体（HGFR, c-Met），ROS1（c-ros），和酪氨酸激酶（RON）的一种抑制剂。

易位可影响ALK基因导致致癌融合蛋白的表达。

ALK融合蛋白的形成导致激活和基因表达和增加细胞增殖有贡献信号的调节异常而生存肿瘤表达这些蛋白。

克唑替尼就是通过阻断对肿瘤细胞生长与存活起关键作用的多种细胞通路，导致肿瘤的稳定或消退。

药物Crizotinib(克唑替尼)合成检索总结报告

药物Crizotinib（克唑替尼）合成检索总结报告
一、Crizotinib（克唑替尼）简介
Crizotinib（克唑替尼）是ATP竞争性的多靶点蛋白激酶抑制剂。

Crizotinib（克唑替尼）分别在ALK、ROS和MET激酶活性异常的肿瘤患者中证实克唑替尼对人体有显著临床疗效，适用于间变性淋巴瘤激酶阳性的局部晚期等。

Crizotinib（克唑替尼）分子结构式如下:
英文名称：Crizotinib
中文名称：克唑替尼
本文主要对Crizotinib（克唑替尼）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。

二、Crizotinib（克唑替尼）合成路线
Crizotinib（克唑替尼）19合成路线一：
Crizotinib（克唑替尼）19合成路线二：
三、Crizotinib（克唑替尼）合成检索总结报告(一) Crizotinib（克唑替尼）中间体3的合成方法一
(二) Crizotinib （克唑替尼）中间体3的合成方法二
(三) Crizotinib （克唑替尼）中间体5的合成
(四) Crizotinib（克唑替尼）中间体6的合成方法一。

ALK基因突变和对应靶向药物

间变性淋巴瘤激酶（ALK）突变的形式有过量表达、与其他基因形成融合基因，发生点突变等等。

ALK基因融合突变是非小细胞肺癌（NSCLC）常见的一种驱动基因，中国非小细胞肺腺癌中ALK融合突变阳性的比例为5.3%，在非小细胞肺腺癌、年轻患者（小于60岁）以及不吸烟的人群中发生率较高，ALK阳性的非小细胞肺癌被认为是一种分子亚型，相对应的靶向药物与EGFR分子亚型完全不同。

ALK融合基因突变主要在肺腺癌里常见，一般肺鳞癌患者ALK融合基因突变概率很低，有报道说1400个肺鳞癌患者里ALK融合基因的发生率为1.3%。

考虑到ALK总体突变频率仅有5%，所以对于鳞癌患者也是可以做一下ALK检测的。

由于非小细胞肺癌里的驱动基因突变一般是互相排斥的，或者说一山不容二虎，癌细胞也没有必要搞两个驱动突变。

有研究说亚裔的EGFR、KRAS野生型的腺癌患者，ALK阳性比例高达30%-42%，因此如果发现EGFR 和KRAS是野生型，是更有必要测下ALK基因的。

一、ALK融合突变的检测图1：非小细胞肺癌中ALK的重排形式据报道，目前已发现21种EML4-ALK的融合形式，另外ALK还可能与TFG、KIF5B、KLC1、PTPN3、STRN等基因发生融合，因此ALK融合突变的诊断是存在一定难度的。

下表是关于ALK融合突变的诊断方法，及其相应的特点。

表1：ALK基因检测的方法需要注意，临床常用的三种方法是FISH、Ventana IHC及RT-PCR，三种方法FISH的灵敏度最低。

因此，如果是胸腔积液、细针穿刺取到的细胞学样本做成的蜡块，不建议使用FISH，避免假阴性。

另外通过抽血检测循环肿瘤DNA（ctDNA），循环肿瘤细胞（CTC）也正在发展起来。

总之在面对ALK检测结果模棱两可的时候，一定要换一个检测方法去验证，也没有哪一种方法灵敏度和特异性都是100%。

二、ALK的靶向药物ALK融合突变阳性的患者使用克唑替尼可以获益，克唑替尼具有ALK、c-MET、ROS1三个靶点。