Blum Robert A, Majumdar Anup, McCrea Jacqueline, Busillo John, Orlowski Laura H, Panebianco Deborah, Hesney Michael, Petty Kevin J, Goldberg Michael R, Murphy M Gail, Gottesdiener Kevin M, Hustad Carolyn M, Lates Christian, Kraft Walter K, Van Buren Sandi, Waldman Scott A, Greenberg Howard E
Buffalo Clinical Research Center, Buffalo, New York, USA
Clin Ther. 2003 May;25(5):1407-19. doi: 10.1016/s0149-2918(03)80128-5.
The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV).
Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV.
The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )), peak plasma concentration, and apparent terminal elimination half-life (t(12)) of both ondansetron and granisetron.
Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of aprepitant 375 mg produced a small but statistically significant increase in the AUC(0- infinity ) for intravenous ondansetron (from 1268.3 to 1456.5 ng.h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with aprepitant vs 408.4 ng/mL without) or t(12) (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC(0- infinity ), 101.4 ng.h/mL with aprepitant vs 92.2 ng.h/mL without; maximum plasma concentration, 9.0 ng/mL with and without aprepitant; time to maximum plasma concentration, both 3.0 hours; t(12), 6.5 vs 6.9 hours, respectively).
Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.
神经激肽-1受体拮抗剂阿瑞匹坦与皮质类固醇和5-羟色胺3型（5-HT(3)）受体拮抗剂联合使用时，已被证明可有效预防急性和迟发性化疗引起的恶心和呕吐（CINV）。
进行两项研究以确定阿瑞匹坦的联合使用是否会改变昂丹司琼和格拉司琼的药代动力学特征，这两种5-HT(3)受体拮抗剂常用于CINV的止吐治疗。
这两项研究为随机、开放标签、交叉试验，在18至46岁的健康受试者中进行。研究1涉及以下两种治疗方案：第1天口服阿瑞匹坦375mg、地塞米松20mg及静脉注射昂丹司琼32mg，随后在第2至5天口服阿瑞匹坦250mg及地塞米松8mg；以及第1天口服地塞米松20mg及静脉注射昂丹司琼32mg，随后在第2至5天口服地塞米松8mg。研究2涉及以下两种治疗方案：第1天口服阿瑞匹坦125mg与格拉司琼2mg，随后在第2天和第3天口服阿瑞匹坦80mg；以及仅在第1天口服格拉司琼2mg。使用个体血浆样本估计昂丹司琼和格拉司琼从时间零点至无穷大的血浆浓度-时间曲线下面积（AUC(0-无穷大)）、血浆峰浓度及表观末端消除半衰期（t(12)）。
研究1纳入19名受试者（10名女性，9名男性），研究2纳入18名受试者（11名男性,7名女性）。联合使用375mg阿瑞匹坦使静脉注射昂丹司琼的AUC(0-无穷大)有小幅但具有统计学意义的增加（从1268.3增至1456.5ng·h/mL；P = 0.019），对输注结束时的峰浓度（联合阿瑞匹坦时为360.8ng/mL，未联合时为408.4ng/mL）或t(12)（分别为5.0小时和4.5小时）无显著影响。联合使用125mg/80mg阿瑞匹坦未改变口服格拉司琼的平均药代动力学特征（AUC(0-无穷大)，联合阿瑞匹坦时为101.4ng·h/mL，未联合时为92.2ng·h/mL；最大血浆浓度，联合与未联合阿瑞匹坦时均为9.0ng/mL；达到最大血浆浓度的时间，均为3.0小时；t(12)，分别为6.5小时和6.9小时）。
在这些健康受试者中，联合使用阿瑞匹坦对昂丹司琼或格拉司琼的平均药代动力学特征无临床显著影响。
