An FDA Approved Neurokinin-1 Receptor Antagonist is Effective in Reducing Intraabdominal Adhesions when Administered Intraperitoneally,But Not Orally

Introduction  Postoperative adhesions pose a continued healthcare problem. We previously demonstrated that intraperitoneal (IP) administration of a neurokinin-1 receptor antagonist (NK-1RA) at surgery reduces intraabdominal adhesions in rats. The NK-1RA aprepitant (Emend™, Merck) is clinically approved for preventing postoperative nausea and vomiting; however, its effects on adhesion formation are unknown. Thus, we determined the effects of IP and oral administration of aprepitant on adhesion formation in a rat model. Methods  Adhesions were surgically induced in rats that were randomized to receive either one or five oral preoperative doses or a single intraoperative IP dose of aprepitant (50 mg/kg). Adhesions were scored at 7 days. In similar experiments using IP dosing, animals were sacrificed at 24 h and peritoneal fluid, and tissue were collected to assess fibrinolytic activity and tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA levels, respectively. Results  IP aprepitant reduced adhesion formation by 33% (p < 0.05) compared with controls while oral aprepitant had no effect. Compared to controls IP aprepitant reduced tPA activity by 55% (p < 0.05), increased PAI-1 mRNA levels by 140% (p < 0.05), and had no affect on tPA mRNA levels. Conclusion  These data suggest that aprepitant maybe a useful pharmacologic agent for reducing adhesion formation clinically. This work was supported in part, by Merck, Rahway, NJ, USA and by the Smithwick Endowment Fund to the Department of Surgery at Boston University School of Medicine. Presented, in part, at the third Annual Academic Surgical Congress Feb 12–15th, 2008, Huntington Beach, CA, USA An erratum to this article can be found at     

Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): A multicentre,randomised, controlled phase 3 trial

IntroductionThe oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin.MethodsIn this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT₃-receptor antagonist + dexamethasone) or aprepitant group (5-HT₃-receptor antagonist + dexamethasone + aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis.ResultsA total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups.ConclusionThe aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.     

Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

Background: Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported. Patients and methods: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m²/day), thiotepa (120 mg/m²/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. Results: In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC₅₀) of aprepitant for inhibition of cyclophosphamide (IC₅₀=1.3 g/ml) and thiotepa (IC₅₀=0.27 g/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001). Conclusion: Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.     

Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients

Background Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4.Methods A total of 11 cancer patients (4 male, 7 female, aged 50–68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60–100 mg/m², on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14.Results Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC_0–last was 3.26 vs 3.17 g h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC_0– 3.51 vs 3.39 g h/ml (P>0.25; ratio B/A 0.96); geometric mean C_max was 3.53 vs 3.37 g/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m² (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm³ during treatment with docetaxel alone and 975/mm³ during aprepitant coadministration.Conclusions Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4.     

Preventing postoperative nausea and vomiting: post hoc analysis of pooled data from two randomized active-controlled trials of aprepitant

ABSTRACT

Objective: Compared with the 5HT₃ antagonist ondansetron, the NK₁ antagonist aprepitant has been shown in two double-blind trials to provide greater protection against postoperative vomiting and comparable or greater control of nausea. Post hoc analyses of pooled data from these trials were performed to more fully characterize the efficacy profile of aprepitant in terms of nausea and use of rescue therapy.

Research design and methods: Patients (n = 1599) scheduled for major surgery under general anesthesia (primarily gynecological surgery) were assigned to receive a preoperative dose of aprepitant 40?mg PO, 125?mg PO, or ondansetron 4?mg IV. in two randomized, double-blind, clinical trials.

Main outcome measures: Post-surgery vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale).

Results: In the 24 hours after surgery, aprepitant 40?mg was more effective than ondansetron for all five endpoints evaluated: (1) no significant nausea (56.4% vs. 48.1%); (2) no nausea (39.6% vs. 33.1%); (3) no vomiting (86.7% vs. 72.4%); (4) no nausea and no vomiting (38.3% vs. 31.4%); and (5) no nausea, no vomiting, and no use of rescue (37.9% vs. 31.2%) (?p < 0.035 for the odds ratio for each comparison). Numerically more patients receiving aprepitant 125?mg also achieved these endpoints compared with ondansetron.

Conclusions: These post hoc analyses confirm the favorable efficacy profile of aprepitant for the prevention of postoperative nausea and vomiting.     

Aprepitant exerts anti-fibrotic effect via inhibition of TGF-β/Smad3 pathway in bleomycin-induced pulmonary fibrosis in rats

Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-β) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-β, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.     

阿瑞匹坦三联疗法预防中高度催吐风险化疗所致恶心呕吐的疗效观察

目的 对中高度催吐化疗方案分次给药导致的恶心呕吐应用阿瑞匹坦三联方案进行预防的临床疗效以及安全性进行分析。方法 择取我院在2015年5月至2017年5月接收的进行中高度催吐化疗癌症患者80例进行治疗研究,按数字奇偶法进行临床分组,其中对照组48例给予传统预防,实验组52例给予阿瑞匹坦三联疗法进行预防;观察两组患者第一次发生恶心呕吐平均时间值,呕吐生活功能评分,预防效果以及阿瑞匹坦三联方案用药安全性。结果 实验组患者第一次发生恶心呕吐时间相较于对照组明显延长,且数据差异显著（p＜0.05）;实验组生活功能评分较对照组改善明显（p＜0.05）;实验组临床预防缓解率为92.30%,对照组临床预防缓解率为79.17%,实验组显著优于对照组,差异具有统计学意义（p＜0.05）;实验组头晕、乏力、便秘、焦虑等不良反应发生率为13.46%,高于对照组的12.50%,但两组患者不良反应发生数据对比,并无统计学意义（p＞0.05）。结论 对中高度催吐化疗方案导致的恶心呕吐癌症患者给予阿瑞匹坦三联方案进行预防,可延长患者第一次恶心呕吐发生时间,预防效果显著且生活质量明显改善,安全性高,值得临床推广应用。     

阿瑞吡坦联合昂丹司琼及地塞米松防治直肠癌患者术后化疗相关性恶心呕吐临床观察

摘 要 目的：探讨阿瑞吡坦联合昂丹司琼及地塞米松防治直肠癌患者术后mFOLFOX6方案化疗相关性恶心呕吐的临床疗效。方法：122例接受术后mFOLFOX6方案化疗的直肠癌患者随机分入观察组（阿瑞吡坦+昂丹司琼+地塞米松）和对照组（昂丹司琼+地塞米松）进行预防性止吐。记录患者恶心、呕吐及其他不良反应,并评估化疗相关性恶心呕吐对患者生活质量的影响。结果：观察组急性呕吐和延迟性呕吐控制有效率分别为80.0%和83.3%,均显著优于对照组（P<0.05）。两组恶心控制有效率差异无统计学意义（P >0.05）。观察组患者生活质量评分显著高于对照组（P＜0.01）,且观察组对生活质量产生负面影响的人数明显少于对照组（P＜0.01）。结论：阿瑞吡坦联合昂丹司琼及地塞米松对术后mFOLFOX6方案化疗的直肠癌患者发生呕吐的控制作用显著,同时能改善患者的生活质量,且未造成更多不良反应。     

阿瑞匹坦对黑色素瘤患者顺铂治疗引起恶心呕吐的止吐作用

目的 旨在探讨阿瑞匹坦对黑色素瘤患者顺铂治疗引起的恶心呕吐的作用。方法 170例接受含顺铂方案治疗的黑色素瘤患者,随机分入阿瑞匹坦组和对照组进行预防性止吐治疗。记录患者顺铂治疗后的恶心、呕吐反应,解救治疗,功能性生活指数（呕吐）及其他不良反应。结果 两组中各84例患者可评价疗效。阿瑞匹坦组患者的完全缓解率（无呕吐,无解救治疗）为69%,显著高于对照组的44%（χ²=10.683,P=0.001）。阿瑞匹坦组和对照组的呕吐发生率分别为27%和51%,阿瑞匹坦组显著优于对照组（χ²=9.982,P=0.002）。阿瑞匹坦组未观察到相关的不良反应。结论 阿瑞匹坦可显著降低黑色素瘤患者中顺铂引起的呕吐反应。尽管阿瑞匹坦的安全性良好,在给药前仍需注意药物间的相互作用。