Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833

作者：Isagani Chico, Min H. Kang, Raymond C. Bergan, Jame Abraham, Susan Bakke, Beverly Meadows, Ann Rutt, Robert W. Robey, Peter L. Choyke, Maria Merino, Barry R. Goldspiel, Tom Smith, Seth M. Steinberg, William D. Figg, Tito Fojo, Susan E. Bates · 发表于：Journal of Clinical Oncology · 年份：2001 · DOI：10.1200/jco.2001.19.3.832 · 被引用次数：89 · 研究领域：Drug Transport and Resistance Mechanisms、Nanoparticle-Based Drug Delivery、Cancer Treatment and Pharmacology

PURPOSE: PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. PATIENTS AND METHODS: Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. RESULTS: In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patie...