van Warmerdam L J, Huizing M T, Giaccone G, Postmus P E, ten Bokkel Huinink W W, van Zandwijk N, Koolen M G, Helmerhorst T J, van der Vijgh W J, Veenhof C H, Beijnen J H
European Cancer Centre, Amsterdam, The Netherlands.
Semin Oncol. 1997 Feb;24(1 Suppl 2):S2-97-S2-104.
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.
在两项一期研究中，对83例既往未接受过治疗的非小细胞肺癌或卵巢癌患者，研究了卡铂（C）与紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）（P）联合应用的临床药理学。卡铂静脉输注30分钟，紫杉醇静脉输注3小时。两种药物均每4周给药一次。非小细胞肺癌患者随机分为两种给药顺序，即先给予卡铂后给予紫杉醇（C→P）或相反顺序（P→C）。每位患者在第二个疗程及后续疗程接受交替顺序给药。卵巢癌患者均先接受紫杉醇治疗，后接受卡铂治疗。通过无火焰原子吸收光谱法测定血浆超滤液中的铂浓度，共获得122条浓度-时间曲线。对于非小细胞肺癌患者，每300mg/m²卡铂的浓度-时间曲线下平均面积（AUC），C→P顺序为3.52mg/mL·min（范围1.94至5.83），P→C顺序为3.62mg/mL·min（范围1.91至5.01）。未观察到顺序依赖性效应（P>.5）。对于卵巢癌患者，每300mg/m²卡铂的平均AUC为3.83mg/mL·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 = 0.13）。此外，将紫杉醇剂量从100mg/m²增加至250mg/m²，并未影响卡铂的AUC。中性粒细胞减少是主要毒性反应，贫血也较为常见。然而，血小板减少症明显少见。对卡铂AUC与血小板减少之间的关系进行建模显示，卡铂AUC为6.3mg/mL·min（AUC50）时，血小板减少50%。这与既往记录的卡铂AUC50为4.0mg/mL·min的数据形成对比。我们的研究结果表明，两种药物在细胞水平存在显著相互作用，卡铂对紫杉醇的主要血液学毒性（即中性粒细胞减少）至少具有相加作用。紫杉醇对卡铂相关毒性（即血小板减少）也具有保护作用。紫杉醇在该联合用药中具有明确的保护作用，提示有可能将给药间隔缩短至3周。目前正在进行研究以验证这一假设，并探究潜在的药理相互作用。
