Bates S, Kang M, Meadows B, Bakke S, Choyke P, Merino M, Goldspiel B, Chico I, Smith T, Chen C, Robey R, Bergan R, Figg W D, Fojo T
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Cancer. 2001 Sep 15;92(6):1577-90. doi: 10.1002/1097-0142(20010915)92:6<1577::aid-cncr1484>3.0.co;2-h.
PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion.
Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study.
The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response.
PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.
PSC 833是一种第二代P-糖蛋白（Pgp）拮抗剂，旨在逆转多药耐药性（MDR）。作者开展了一项I期研究，口服PSC 833联合长春花碱，长春花碱采用5天持续输注给药。
79例晚期恶性疾病患者入组该试验，并接受递增剂量的PSC 833治疗。预计PSC 833与长春花碱之间会发生药代动力学相互作用。因此，当观察到剂量限制性毒性时，随着PSC 833剂量的增加，长春花碱的剂量会降低。该研究使用了三种给药方案和两种PSC 833制剂。
对于液体制剂，PSC 833的最大耐受剂量为每12小时口服12.5 mg/kg，共8天，联合长春花碱每日0.9 mg/m²持续静脉输注（CIV）5天；对于微乳剂，PSC 833的最大耐受剂量为每6小时口服4 mg/kg，共8天，联合长春花碱每日0.6 mg/m² CIV 5天。PSC 833的主要毒性为共济失调和感觉异常，联合用药的主要毒性为便秘、发热和中性粒细胞减少。微乳剂制剂观察到口服生物利用度增加以及峰浓度和谷浓度升高。观察到患者间药代动力学参数存在显著差异。在PSC 833的最大耐受剂量（每6小时口服4 mg/kg，共8天）下研究的10例患者中，作为Pgp拮抗作用的替代指标，观察到若丹明从CD56阳性外周淋巴细胞的流出受到抑制。在43例可评估的肾透明细胞癌患者中，3例完全缓解，1例部分缓解。
只要根据药代动力学相互作用调整长春花碱剂量，PSC 833联合长春花碱可安全用于患者。患者间的高变异性是一个显著的混杂因素。对CD56阳性细胞的替代研究表明，在临床环境中可实现Pgp抑制。改进预测药代动力学相互作用的方法应能改善未来的研究。
