英文药名：Vitrakvi （larotrectinib  Capsules and Oral Solution）

中文药名：拉罗替尼胶囊/口服溶液

生产商：拜耳医药
药品介绍
近日，欧美批准Vitrakvi（larotrectinib），口服TRK抑制剂，用于治疗成人和小儿具有神经营养受体酪氨酸激酶（治疗NTRK）基因融合的实体瘤治疗。Vitrakvi是首个获批准的第一个不区分肿瘤来源用于初始治疗的方法。
批准日期：2018年11月26日 公司：BayerHealthCare Pharmaceuticals Inc
VITRAKVI(拉罗替尼[larotrectinib])胶囊，供口服使用
VITRAKVI(拉罗替尼[larotrectinib])溶液，供口服使用
美国初步批准日期:2018年
作用机制
Larotrectinib是原肌凝蛋白受体激酶(TRK)、TRKA、TRKB和trkc的抑制剂。在广泛的纯化酶分析中，larotrectinib抑制TRKA、TRKB和trkc, IC50值在5-11 nM之间。另一种激酶TNK2被抑制在大约100倍的高浓度。TRKA、B和C由genesNTRK1、NTRK2和NTRK3编码。染色体重排涉及这些基因与不同伴侣的框内融合，可导致本构激活嵌合TRK融合蛋白.
这可以作为一个致癌的驱动因素，促进细胞增殖和肿瘤细胞系的生存。
在体外和体内肿瘤模型中，larotrectinib在TRK蛋白本构激活的细胞中表现出抗肿瘤活性，这些细胞由基因融合、蛋白调控区域的缺失或TRK蛋白过表达引起。Larotrectinib在TRKA激酶域点突变的细胞系中活性最低，包括临床鉴定的获得性抗性突变G595R。TRKC激酶域的点突变包括G623R、G696A和F617L，临床上已确认对larotrectinib产生耐药。
适应症和用法
VITRAKVI是一种激酶抑制剂，适用于成人和儿童实体瘤患者的治疗:
•具有神经营养受体酪氨酸激酶(NTRK)基因融合，无aknown获得性耐药突变，
•是否转移或手术切除可能导致严重出血率，以及;
•没有令人满意的替代治疗或后续治疗有进展。
该指示是在基于总体响应率和响应持续时间的加速审批下批准的。持续批准该指标可能取决于临床疗效验证和验证性试验的描述。
剂量和管理
•根据aNTRK基因融合的存在，选择患者进行VITRAKVI治疗。
•成人和儿童体表表面积大于1.0米方的患者推荐剂量:每日口服两次，每次100毫克。
•儿童体表面积小于1.0米方的患者推荐剂量:每日2次口服100mg/m2。
剂型和强度
•胶囊:25mg、100mg
•口服:20mg/mL
禁忌症
没有。
警告和预防措施
•神经毒性:建议患者和护理人员注意神经系统不良反应的风险。建议有神经毒性的病人不要驾驶或操作危险的机器。保留和修改剂量，或根据严重程度永久停用VITRAKVI。
•肝毒性:在治疗的第一个月，每2周监测一次包括ALT和AST在内的肝脏测试，然后按临床指示每月监测一次。保留和修改剂量，或根据严重程度永久停用VITRAKVI。
•胚胎-胎儿毒性:可引起胎儿损害。建议对胎儿有潜在生殖风险的女性使用有效的镇痛药。
不良反应
最常见的不良反应(≥20%)和VITRAKVI疲劳、恶心、眩晕、呕吐、增加AST,咳嗽、ALT增加,便秘和腹泻。
药物的相互作用
•强CYP3A4抑制剂:避免与VITRAKVI同时使用强CYP3A4inhibitors。如果不能避免联用，应减少VITRAKVI剂量。
•强CYP3A4诱导剂:避免与VITRAKVI同时使用强CYP3A4诱导剂。如果不能避免联用，增加VITRAKVI剂量。
•敏感CYP3A4底物:避免敏化yp3a4底物与VITRAKVI共服。
在特定人群中使用
•哺乳期:建议不要母乳喂养。
•肝损害:中度(Child-Pugh B)至重度(Child-Pugh C)肝损害患者，减少VITRAKVI的起始剂量。
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Vitrakvi（larotrectinib）
Indication
VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that:
have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation,are metastatic or where surgical resection is likely to result in severe morbidity, andhave no satisfactory alternative treatments or that have progressed following treatment.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Important Safety Information
Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurological adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).
Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.
Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.
Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.
Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.
Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.
Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).
Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.
https://www.hcp.vitrakvi-us.com/#indication