Clinical pharmacology of carboplatin administered in combination with paclitaxel.
Clinical pharmacology of carboplatin administered in combination with paclitaxel.
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卡铂与紫杉醇联合用药的临床药理学。
作者：
L. V. van Warmerdam;M. Huizing;G. Giaccone;P. Postmus;W. W. ten Bokkel Huinink;N. van Zandwijk;M. Koolen;T. Helmerhorst;W. van der Vijgh;C. Veenhof;J. Beijnen
卡铂(C)与紫杉醇（Taxol; Bristol-Myers Squibb Company, Princeton， NJ） (P)联合使用的临床药理学在两项I期研究中进行了研究，该研究在83名未经治疗的非小细胞肺癌或卵巢癌患者中进行。卡铂治疗30分钟，紫杉醇治疗3小时。两种药物每4周服用一次。非小细胞肺癌患者被随机分配到两种给药序列，卡铂加紫杉醇（C- >P）或相反（P- >C）。每个患者在第二疗程和随后的疗程中接受交替顺序。卵巢癌患者均在卡铂治疗前接受紫杉醇治疗。采用无焰原子吸收光谱法测定了血浆超滤液中铂的浓度，得到了122条浓度-时间曲线。对于非小细胞肺癌患者，每300 mg/m2卡铂浓度-时间曲线下的平均面积（AUC）对于序列C—>P为3.52 mg/mL x min（范围，1.94至5.83），对于序列P—>C为3.62 mg/mL x min（范围，1.91至5.01）。未观察到序列依赖性效应（P < 0.05）。对于卵巢癌患者，每300 mg/m2卡铂的平均AUC为3.83 mg/mL x min（范围2.72至6.10），与非小细胞肺癌患者的数据相比无差异（P = .13）。此外，卡铂AUC不受紫杉醇剂量从100到250 mg/m2增加的影响。中性粒细胞减少是主要的毒性，贫血是常见的。然而，明显缺乏血小板减少症。卡铂AUC与血小板减少之间的关系建模显示，当卡铂AUC （AUC50）为6.3 mg/mL x min时，血小板减少50%。这与记录卡铂AUC50为4.0 mg/mL x min的历史数据形成对比。我们的研究结果表明，两种药物在细胞水平上存在相当大的相互作用，至少卡铂对紫杉醇的主要血液学毒性（即中性粒细胞减少）具有加性作用。紫杉醇对卡铂相关毒性（即血小板减少）也有保护作用。紫杉醇在这种组合中的明显保护作用表明，将剂量间隔缩短至3周是可能的。研究正在进行中，以验证这一假设，并调查潜在的药理学相互作用。
The clinical pharmacology of carboplatin (C) administered with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) (P) was investigated in two phase I studies undertaken in 83 previously untreated patients with either non-small cell lung cancer or ovarian cancer. Carboplatin was administered over 30 minutes and paclitaxel over 3 hours. Both agents were given every 4 weeks. Non-small cell lung cancer patients were randomized to two administration sequences, either carboplatin followed by paclitaxel (C-->P) or the reverse (P-->C). Each patient received the alternate sequence during the second and subsequent courses. Ovarian cancer patients uniformly received paclitaxel before carboplatin. Platinum concentrations in plasma ultrafiltrate were measured via flameless atomic absorption spectrometry, and 122 concentration-time curves were obtained. For non-small cell lung cancer patients, the mean area under the concentration-time curve (AUC) per 300 mg/m2 carboplatin was 3.52 mg/mL x min (range, 1.94 to 5.83) for the sequence C-->P and 3.62 mg/mL x min (range, 1.91 to 5.01) for the sequence P-->C. No sequence-dependent effect was observed (P > .5). For ovarian cancer patients, the mean AUC per 300 mg/m2 carboplatin was 3.83 mg/mL x min (range, 2.72 to 6.10), showing no difference when compared with data derived from non-small cell lung cancer patients (P = .13). In addition, the carboplatin AUC was not influenced by increasing paclitaxel doses from 100 to 250 mg/m2. Neutropenia was the principal toxicity, and anemia was frequent. However, there was a striking lack of thrombocytopenia. Modeling of the relationship between the carboplatin AUC and the decrease in platelets revealed a 50% decrease in platelets at a carboplatin AUC (AUC50) of 6.3 mg/mL x min. This contrasts with historical data documenting a carboplatin AUC50 of 4.0 mg/mL x min. Our findings suggest that there is a considerable interaction of both drugs at the cellular level, with at least an additive effect of carboplatin on the main hematologic toxicity of paclitaxel (ie, neutropenia). There is also a protective effect exerted by paclitaxel on carboplatin-related toxicity (ie, thrombocytopenia). The clear protective effect of paclitaxel in this combination suggests that it is possible to reduce the dose interval to 3 weeks. Studies are in progress to test this hypothesis and to investigate the underlying pharmacologic interactions.