Tolcher A W, Cowan K H, Solomon D, Ognibene F, Goldspiel B, Chang R, Noone M H, Denicoff A M, Barnes C S, Gossard M R, Fetsch P A, Berg S L, Balis F M, Venzon D J, O'Shaughnessy J A
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Clin Oncol. 1996 Apr;14(4):1173-84. doi: 10.1200/JCO.1996.14.4.1173.
We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer.
Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy.
The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations.
r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.
我们对转移性乳腺癌的重度预处理患者进行了一项I期交叉研究，以逐步增加紫杉醇（泰素；百时美施贵宝公司，新泽西州普林斯顿）和心脏毒性较小的立体异构体r-维拉帕米的剂量。
29例对3小时输注紫杉醇耐药的患者，在相同剂量的3小时紫杉醇输注前24小时开始，每4小时口服r-维拉帕米，共持续12剂。一旦确定了联合用药的最大耐受剂量（MTD），另外7例未接受过任何一种药物治疗的患者接受评估，以确定添加r-维拉帕米是否会改变紫杉醇的药代动力学。同意参与的患者在接受紫杉醇治疗前以及对紫杉醇治疗耐药后，进行肿瘤活检以检测P-糖蛋白（Pgp）表达。
联合用药的MTD为每4小时225mg/m²的r-维拉帕米，同时3小时输注200mg/m²的紫杉醇。在接受250mg/m² r-维拉帕米治疗的5例患者中，有3例出现了剂量限制性低血压和心动过缓。14例患者在门诊接受了32个周期的MTD剂量的r-维拉帕米治疗，未出现心脏毒性。MTD时血清维拉帕米浓度的中位数峰值和谷值分别为5.1μmol/L（范围1.9至6.3），这在体外调节Pgp介导的多药耐药（MDR）所需的范围内。肝转氨酶和胆红素水平升高的患者中，血清维拉帕米浓度升高和心脏毒性的发生更为频繁。与之前未使用r-维拉帕米的紫杉醇周期相比，紫杉醇与r-维拉帕米联合使用时的血液学毒性明显更严重。在药代动力学分析中，r-维拉帕米延迟了紫杉醇的平均清除率，并提高了紫杉醇的平均峰值浓度。
每4小时口服225mg/m²的r-维拉帕米与3小时输注200mg/m²的紫杉醇联合使用时，可作为门诊治疗安全给药，且与被认为对Pgp抑制有效的血清水平相关。添加r-维拉帕米显著改变了紫杉醇的毒性和药代动力学。
