Barbour S, Smit T, Wang X, Powers D, Arora S, Kansra V, Aapro M, Herrstedt J
Department of Pharmacy, Duke University Hospital, Durham, USA.
The Medical Oncology Center of Rosebank, Johannesburg, South Africa.
Ann Oncol. 2017 Jun 1;28(6):1268-1273. doi: 10.1093/annonc/mdx073.
Rolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP.
Patients were randomized to receive either 180 mg oral rolapitant or placebo ∼1-2 h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs.
In the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations.
The results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.
罗拉匹坦是一种长效神经激肽（NK）1受体拮抗剂（RA），已证明在接受中度或高度致吐性化疗的患者中预防化疗引起的恶心和呕吐有效。与其他NK1 RA不同，罗拉匹坦不抑制或诱导细胞色素P450（CYP）3A4，但它确实抑制CYP2D6和乳腺癌耐药蛋白（BCRP）。为了分析罗拉匹坦与同时使用的药物之间潜在的药物相互作用，这项对四项罗拉匹坦双盲、随机II期或III期研究的综合安全性分析，通过使用或不使用CYP2D6或BCRP的药物底物来检查不良事件（AE）。
患者在化疗前约1 - 2小时随机接受180毫克口服罗拉匹坦或安慰剂，同时联合5 - 羟色胺3型RA和地塞米松。在四个研究中汇总了第1周期期间治疗中出现的不良事件（TEAE）和治疗中出现的严重不良事件（TESAEs）的数据，并在总体人群中以及根据是否同时使用CYP2D6或BCRP底物药物进行了总结。
在综合安全人群中，罗拉匹坦组1294例患者中有828例（64%），对照组1301例患者中有840例（65%）经历了至少一次TEAE。罗拉匹坦组和对照组中常见TEAE的频率相似。总体而言，53%的患者接受了CYP2D6底物药物，其中没有一种具有窄治疗指数（如硫利达嗪或匹莫齐特），63%的患者接受了BCRP底物药物。当根据是否同时使用CYP2D6或BCRP底物药物进行分组时，罗拉匹坦组和对照组中TEAE和TESAEs的发生频率相似。
本研究结果支持罗拉匹坦作为接受致吐性化疗患者的止吐三联药物方案一部分的安全性，包括那些同时使用CYP2D6或BCRP底物药物（如昂丹司琼、多西他赛或伊立替康）的患者。
