Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Adv Ther. 2019 Feb;36(2):355-364. doi: 10.1007/s12325-018-0862-2. Epub 2019 Jan 3.
Aprepitant, a selective neurokinin-1 receptor antagonist approved for prevention of chemotherapy-induced nausea and vomiting (CINV), is an inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is involved in the clearance of several chemotherapeutic agents. Here we evaluated the efficacy and toxicity of a combination of aprepitant, palonosetron, and dexamethasone as antiemetic prophylaxis in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy, and examined the potential of aprepitant to affect the pharmacokinetics of ifosfamide, which is primarily metabolized by CYP3A4.
A total of 108 sarcoma patients were randomly assigned to either the aprepitant group (antiemetic regimen: aprepitant, palonosetron, and dexamethasone) or the control group (antiemetic regimen: palonosetron and dexamethasone). Data on nausea, vomiting, and use of rescue medication were collected, and the primary efficacy end point was the proportion of patients with complete response (CR), defined as no vomiting and no use of rescue therapy during 120 h after initiation of chemotherapy. Tolerability was evaluated on the basis of reported adverse events and laboratory assessments. Blood samples for ifosfamide pharmacokinetic analysis were collected in ten patients.
The percentage of patients achieving CR was significantly higher in the aprepitant group compared with that in the control group in the acute, delay, and overall phase (78.4% vs. 59.3%, 74.5% vs. 48.1%, and 68.6% vs. 37.0%, p < 0.05, respectively). No significant differences of adverse events or hematological toxicity were detected between the two groups. Concomitant administration of aprepitant did not cause any statistically significant changes in ifosfamide pharmacokinetics. Values for aprepitant group vs. control group were as follows: geometric mean of C was 119 vs. 120 ng/mL, AUC was 648 vs. 635 ng h/mL, AUC was 681 vs. 668 ng h/mL, plasma clearance was 4.40 vs. 4.49 (L/h/m), respectively; harmonic means of t was 2.11 vs. 2.25 h.
This study showed that aprepitant in combination with palonosetron and dexamethasone was safe and effectively controlled CINV in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy. Aprepitant may have a low potential to affect the pharmacokinetics of chemotherapeutic agents metabolized by CYP3A4.
阿瑞匹坦是一种神经激肽-1 受体拮抗剂，用于预防化疗引起的恶心和呕吐（CINV），它是细胞色素 P450 3A4（CYP3A4）酶的抑制剂，该酶参与清除多种化疗药物。在这里，我们评估了阿瑞匹坦、帕洛诺司琼和地塞米松联合作为接受异环磷酰胺和多柔比星化疗的肉瘤患者止吐预防的疗效和毒性，并研究了阿瑞匹坦对异环磷酰胺药代动力学的潜在影响，而异环磷酰胺主要由 CYP3A4 代谢。
共有 108 例肉瘤患者被随机分配至阿瑞匹坦组（止吐方案：阿瑞匹坦、帕洛诺司琼和地塞米松）或对照组（止吐方案：帕洛诺司琼和地塞米松）。收集恶心、呕吐和使用解救药物的数据，主要疗效终点是完全缓解（CR）患者的比例，定义为在开始化疗后 120 小时内无呕吐且无使用解救治疗。耐受性基于报告的不良事件和实验室评估进行评估。在 10 例患者中采集异环磷酰胺药代动力学分析的血样。
与对照组相比，阿瑞匹坦组在急性、延迟和总体期的 CR 患者比例显著更高（78.4%比 59.3%、74.5%比 48.1%和 68.6%比 37.0%，p<0.05）。两组之间未检测到不良事件或血液学毒性的显著差异。阿瑞匹坦的伴随给药未导致异环磷酰胺药代动力学的任何统计学显著变化。阿瑞匹坦组与对照组的值分别为：C 的几何平均值为 119 比 120ng/ml、AUC 为 648 比 635ng·h/ml、AUC 为 681 比 668ng·h/ml、血浆清除率为 4.40 比 4.49（L/h/ml），t 的调和平均值为 2.11 比 2.25h。
这项研究表明，阿瑞匹坦联合帕洛诺司琼和地塞米松用于接受异环磷酰胺和多柔比星化疗的肉瘤患者，安全有效地控制了 CINV。阿瑞匹坦可能对 CYP3A4 代谢的化疗药物的药代动力学有较低的潜在影响。
