Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer
Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer
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DOI：
10.1200/jco.1996.14.10.2713
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发表时间：
1996-10-01
影响因子：
45.3
通讯作者：
Hortobagyi, GN
中科院分区：
文献类型：
--
作者：
Holmes, FA;Madden, T;Hortobagyi, GN
目的：确定是否会发生时间表依赖性相互作用，当pacs患者和方法：10例转移性乳腺癌患者在阿霉素48 mg/m(2) 48小时的初始化疗之前或之后立即接受紫杉醇125 mg/m(2) 24小时的化疗。给予两个疗程，疗程一结束后，给药顺序颠倒。在队列1中，紫杉醇先于阿霉素进行疗程1。在队列2中，阿霉素先于紫杉醇进行疗程1。在输注期间和输注后24小时连续测量阿霉素水平。临床评估患者是否发生口腔炎和感染，并每周检测两次粒细胞计数。结果：8例患者完成了两个疗程的药代动力学采样。紫杉醇-阿霉素组输注结束时血浆多柔比星平均浓度（Cmax）比相反组（45 +/- 8 ng/mL vs 26 +/- 5 ng/mL）高70%。紫杉醇-阿霉素组的平均清除率降低32% （34.3 +/- 10.3 L/h vs 51.6 +/- 16.1 L/h, P < 0.01）。临床上，紫杉醇-阿霉素组血液学和粘膜毒性作用更严重。紫杉醇-阿霉素-紫杉醇组中位绝对粒细胞计数为0.2/ μ L，阿霉素-紫杉醇组中位绝对粒细胞计数为1.3/ μ L， 10例紫杉醇-阿霉素-紫杉醇组中7例为2级（n = 4）或3级（n = 3）口炎，而10例阿霉素-紫杉醇组中只有1例为2级口炎，没有一例为3级口炎。结论：紫杉醇24小时输注在阿霉素48小时输注之前，阿霉素清除率降低近三分之一，导致2级和3级口炎。为防止紫杉醇（24小时输注）和阿霉素先后给药时出现这种情况，应首先给药阿霉素。这种效应的机制正在调查中。(C)美国临床肿瘤学会1996。
Purpose: To determine whether a schedule-dependent interaction occurs when pacPatients and Methods: Ten patients with metastatic breast cancer received paclitaxel 125 mg/m(2) over 24 hours either immediately before or after doxorubicin 48 mg/m(2) over 48 hours as the initial chemotherapy treatment. Two such courses were given, and the sequence of administration was reversed after course 1. In cohort 1, paclitaxel preceded doxorubicin for course 1. In cohort 2, doxorubicin preceded paclitaxel for course 1. Doxorubicin levels were measured serially during the infusion and for 24 hours following it. Patients were assessed clinically for the occurrence of stomatitis and infection, and granulocyte counts were measured twice weekly.Results: Eight patients had complete pharmacokinetic sampling for both courses. The mean end-of-infusion plasma doxorubicin concentrations (Cmax) were 70% higher in the paclitaxel-doxorubicin sequence compared with the reverse sequence (45 +/- 8 ng/mL v 26 +/- 5 ng/mL). The mean doxorubicin clearance was 32% lower in the paclitaxel-doxorubicin sequence (34.3 +/- 10.3 L/h v 51.6 +/- 16.1 L/h, P < .01). Clinically, hematologic and mucosal toxic effects were worse in the paclitaxel-doxorubicin sequence. The median absolute granulocyte count was 0.2/mu L in the paclitaxel-doxorubicin sequence and 1.3/mu L in the doxorubicin-paclitaxel sequence, Seven of 10 patients who received the paclitaxel-doxorubicin sequence had grade 2 (n = 4) or 3 (n = 3) stomatitis, while only one of 10 patients who received the doxorubicin-paclitaxel sequence had grade 2 stomatitis and none had grade 3.Conclusion: When paclitaxel by 24-hour infusion precedes doxorubicin by 48-hour infusion, doxorubicin clearance is reduced by nearly one third, which results in grade 2 and 3 stomatitis. To prevent this effect when paclitaxel (by 24-hour infusion) and doxorubicin are administered sequentially, doxorubicin should be given first. The mechanisms for this effect are under investigation. (C) 1996 by American Society of Clinical Oncology.