Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. The European Cancer Centre.

作者：Manon Thirza Huizing, Giuseppe Giaccone, Laurence JC van Warmerdam, Hilde Rosing, Piet J.M. Bakker, Jan Baptist Vermorken, Pieter E. Postmus, Nico van Zandwijk, Marijn Koolen, Wim W. ten Bokkel Huinink, W J van der Vijgh, F. Bierhorst, Andrew Lai, O. Dalesio, Herbert M. Pinedo, Cees H.N. Veenhof, Jos H. Beijnen · 发表于：Journal of Clinical Oncology · 年份：1997 · DOI：10.1200/jco.1997.15.1.317 · 被引用次数：183 · 研究领域：Cancer Treatment and Pharmacology、Lung Cancer Treatments and Mutations、Lung Cancer Research Studies

PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of paclitaxel (P) and carboplatin (C) in a sequence-finding and dose-escalating study in untreated non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-five chemotherapy-naive patients with NSCLC were entered onto the pharmacokinetic part of a large phase I trial in which P was administered as a 3-hour infusion at dosages of 100 to 250 mg/m2, and C over 30 minutes at dosages of 300 to 400 mg/m2. Patients were randomized for the sequence of administration, first C followed by P or vice versa. Each patient received the alternate sequence during the second and subsequent courses. RESULTS: The most important hematologic toxicity encountered-was neutropenia. Hematologic toxicity was not dependent on the sequence in which P and C were administered, but there was cumulative neutropenia. Nonhematologic toxicities consisted mainly of vomiting, myalgia, and arthralgia. No sequence-dependent pharmacokinetic interactions for the P area under the concentration-time curve (P-AUC), maximal plasma concentration (P-Cmax), or time above a threshold concentration of 0.1 mumol/L (P-T > or = 0.1 mumol/L) were observed. However, there was a significant difference for the metabolite 6 alpha-hydroxypaclitaxel AUC (6OHP-AUC). Higher 6OHP-AUCs were observed when C was administered before P. The mean plasma ultrafiltrate AUC of C (CpUF-AUC) at the dosage of 300 mg/m2 for the sequence C-->P was 3.52 mg/mL.min (range, 1...