Gilbert C J, Petros W P, Vredenburgh J, Hussein A, Ross M, Rubin P, Fehdrau R, Cavanaugh C, Berry D, McKinstry C, Peters W P
Duke University Bone Marrow Transplant Program, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Cancer Chemother Pharmacol. 1998;42(6):497-503. doi: 10.1007/s002800050851.
Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy.
A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h. A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic monitoring of each drug used in the high-dose chemotherapy regimen was conducted.
Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml x min) were lower than those of the control patients (88.3 mg/ml x min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only.
Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine. Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide metabolites so that clinical implications can be addressed.
昂丹司琼和环磷酰胺均被认为通过肝脏微粒体过程进行代谢。本研究的目的是评估昂丹司琼与高剂量烷化剂化疗之间潜在的药代动力学相互作用。
共有54例接受高剂量环磷酰胺、顺铂和卡莫司汀治疗的乳腺癌患者在四个连续队列中进行前瞻性治疗。队列I和II接受昂丹司琼和丙氯拉嗪的持续输注，队列III和IV接受相同剂量的单独昂丹司琼持续输注。所有患者每4小时接受一次劳拉西泮治疗。一组75例匹配的历史对照接受丙氯拉嗪与劳拉西泮的持续输注。对高剂量化疗方案中使用的每种药物进行药代动力学监测。
接受昂丹司琼治疗的患者中环磷酰胺的中位AUC（73.6mg/ml×min）低于对照患者（88.3mg/ml×min，n = 75，P = 0.0004），但顺铂的中位AUC约高10%，且未显示卡莫司汀处置存在差异。接受昂丹司琼治疗的患者头痛发生率高于对照组。在治疗的第一天，昂丹司琼+丙氯拉嗪组实现完全呕吐控制的频率高于单独使用昂丹司琼组，且这两组均高于单独使用丙氯拉嗪组。
当同时给予这些药物时，昂丹司琼改变了环磷酰胺的全身暴露。单独使用昂丹司琼时，总体呕吐控制没有实质性改善，但与丙氯拉嗪联合使用可能改善控制。需要未来的随机研究来阐明昂丹司琼对活性环磷酰胺代谢物处置的影响，以便解决临床问题。
