Lerza R, Vannozzi M O, Tolino G, Viale M, Bottino G B, Bogliolo G, Cerruti A, Castello G, Mencoboni M, Reggiardo G, Pannacciulli I, Esposito M
Dipartimento Medicina Interna, University of Genoa, Italy.
Ann Oncol. 1997 Apr;8(4):385-91. doi: 10.1023/a:1008203100410.
Cisplatin (DDP) and carboplatin (CBDCA) are two of the most effective drugs in a locoregional approach. Since simultaneous combined treatment with intrapleural DDP and CBDCA has not been reported in humans, we investigated its use in patients with malignant effusions, focusing on pharmacokinetics.
The pharmacokinetics of DDP and CBDCA were studied in 10 patients with malignant pleural effusion treated intrapleurally with a combination of DDP (60 mg/m2) and CBDCA (270 mg/m2) and in additional patients who received the same doses of drugs administered intravenously as single agents or in combination. Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP) and intact CBDCA in plasma and pleural fluid ultrafiltrates were measured by means of high performance liquid chromatography and atomic absorption spectrometry.
Both in the plasma and pleural fluid, the total levels of free Pt represented the additive result of the individual concentrations of CBDCA and Pt-species derived from DDP. After intrapleural combination, high pleural-plasma ratios of the peak concentrations and AUCs were observed both for CBDCA and DDP-derived Pt species, highlighting a distinct local pharmacological advantage. However, the Pt species originating from DDP were absorbed more rapidly from the pleural cavity than CBDCA (Ka = 86 x 10(-3) vs. 37 x 10(-3) min-1, P < 0.05). Intrapleural combination of CBDCA and DDP produced therapeutic plasma levels of reactive (free) DDP species and increased the extent of their residence time (MRT) compared with single intravenous DDP treatment [peak concentration: 1.1 +/- 0.1 (SD) vs. 1.6 +/- 0.2 microgram/ml; MRT: 5.2 +/- 1.9 vs. 0.5 +/- 0.06 h]. Furthermore, the plasma AUC of free CBDCA after intrapleural combined treatment (2.1 +/- 0.5 mg/ ml x min) was similar to that after intravenous administration of CBDCA alone (2.1 +/- 0.2 mg/ml x min). The intrapleural treatment was well tolerated by all patients. Toxicity consisted of mild nausea and vomiting (grade 1-2 according to the WHO scale) in four patients. Myelosuppression (grade 1-2) was remarkable only in two heavily pretreated patients. No evidence of recurrence of the pleural effusion was observed in six patients (complete response), while an asymptomatic minimal fluid reaccumulation not requiring drainage (partial response) was observed in four patients.
The pharmacologic results seem to exclude a pharmacokinetic interaction between CBDCA and DDP and suggest that a dose of CBDCA 2-fold higher than that used in this study associated intrapleurally with 60 mg/m2 DDP could induce an acceptable and predictable myelosuppression.
顺铂（DDP）和卡铂（CBDCA）是局部区域治疗中最有效的两种药物。由于尚未见人体同时联合胸腔内应用DDP和CBDCA的报道，我们研究了其在恶性胸腔积液患者中的应用，重点关注药代动力学。
对10例接受胸腔内联合应用DDP（60mg/m²）和CBDCA（270mg/m²）治疗的恶性胸腔积液患者以及另外接受相同剂量药物静脉单药或联合给药的患者进行DDP和CBDCA的药代动力学研究。通过高效液相色谱和原子吸收光谱法测定血浆和胸腔积液超滤液中源自DDP的铂（Pt）物种（代谢物加未改变的DDP）和完整的CBDCA。
在血浆和胸腔积液中，游离Pt的总水平均代表CBDCA和源自DDP的Pt物种各自浓度的相加结果。胸腔内联合给药后，观察到CBDCA和源自DDP的Pt物种的峰值浓度和药时曲线下面积（AUC）的胸腔 - 血浆比值均较高，突出了明显的局部药理学优势。然而，源自DDP的Pt物种从胸腔的吸收比CBDCA更快（Ka = 86×10⁻³ 对 37×10⁻³ min⁻¹，P < 0.05）。与静脉单药DDP治疗相比，胸腔内联合应用CBDCA和DDP产生了治疗性的血浆活性（游离）DDP物种水平，并延长了其停留时间（平均驻留时间，MRT）[峰值浓度：1.1±0.1（标准差）对 1.6±0.2μg/ml；MRT：5.2±1.9对 0.5±0.06小时]。此外，胸腔内联合治疗后游离CBDCA的血浆AUC（2.1±0.5mg/ml·min）与单独静脉给予CBDCA后的AUC（2.1±0.2mg/ml·min）相似。所有患者对胸腔内治疗耐受性良好。毒性表现为4例患者出现轻度恶心和呕吐（根据WHO分级为1 - 2级）。骨髓抑制（1 - 2级）仅在2例既往接受过大量治疗的患者中较为明显。6例患者未观察到胸腔积液复发的证据（完全缓解），4例患者观察到无症状的少量液体再积聚且无需引流（部分缓解）。
药理学结果似乎排除了CBDCA和DDP之间的药代动力学相互作用，并表明与本研究中使用的剂量相比，胸腔内联合60mg/m² DDP时，CBDCA剂量高出2倍可能会诱导可接受且可预测的骨髓抑制。
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