Dando Toni M, Perry Caroline M
Adis International Limited, 41 Centorian Drive, PB 65901, Mairangi Bay, Auckland, New Zealand.
Drugs. 2004;64(7):777-94. doi: 10.2165/00003495-200464070-00013.
Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.
阿瑞匹坦（意美）是一类新型药物——神经激肽NK(1)受体拮抗剂中首个上市的药物。口服阿瑞匹坦与其他药物联合使用，适用于预防成人因高致吐性化疗引起的急性和迟发性化疗所致恶心和呕吐（CINV）。在三项随机、双盲、安慰剂对照试验中，将阿瑞匹坦（第1天125mg，第2天和第3天或第2 - 5天每日80mg）加标准疗法（静脉注射昂丹司琼和口服地塞米松）与标准疗法加安慰剂进行比较，阿瑞匹坦治疗组中总体完全缓解（主要终点，定义为无呕吐且未接受救援治疗）的患者显著更多（63 - 73% 对比43 - 52%，所有比较p < 0.01）。阿瑞匹坦治疗组中在急性和迟发性阶段完全缓解及完全保护的患者，以及总体完全保护的患者也显著更多。治疗组之间的差异在总体和迟发性阶段比在急性阶段更明显。阿瑞匹坦加标准疗法预防CINV的止吐疗效在多达六个化疗周期中得以维持。在进行评估的情况下，与标准疗法加安慰剂组相比，阿瑞匹坦加标准疗法组中有更多患者报告CINV对日常生活无影响，这是通过功能生活指数 - 呕吐量表评估得出的。阿瑞匹坦一般耐受性良好。随机试验中最常见的不良事件是乏力或疲劳。接受阿瑞匹坦治疗的患者经历的其他不良事件包括厌食、便秘、腹泻、恶心（研究第5天后）和打嗝。除了是细胞色素P450（CYP）3A4的底物外，阿瑞匹坦还是该同工酶的中度抑制剂和诱导剂，以及CYP2C9的诱导剂。因此，阿瑞匹坦有可能与其他经肝脏CYP同工酶代谢的药物发生相互作用。在一项试验中，阿瑞匹坦加标准疗法组中严重感染或发热性中性粒细胞减少的发生率高于标准疗法加安慰剂组；这归因于阿瑞匹坦与地塞米松之间的药代动力学相互作用。在随后的试验中，采用了改良的地塞米松方案。总之，当添加到标准疗法（一种5 - 羟色胺5 - HT(3)受体拮抗剂和一种皮质类固醇）中时，阿瑞匹坦在预防成人因高致吐性化疗引起的CINV方面有效且一般耐受性良好。尽管在预防CINV方面取得了显著进展，但标准疗法并不能保护所有患者。在标准疗法中添加阿瑞匹坦为预防成人癌症患者的急性和迟发性CINV带来了进展。
