Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer

M. T. Huizing, G. Giaccone, L. J. van Warmerdam, H. Rosing, P. J. Bakker, J. B. Vermorken, P. E. Postmus, N. van Zandwijk, M. G. Koolen, W. W. ten Bokkel Huinink, W. J. van der Vijgh, F. J. Bierhorst, A. Lai, O. Dalesio, H. M. Pinedo, C. H. Veenhof, J. H. Beijnen

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Abstract

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-C(max)), or time above a threshold concentration of 0.1 μmol/L (P-T ≤ 0.1 μmol/L) were observed. However, there was a significant difference for the metabolite 6α- 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, 1.94 to 5.83) and 3.62 mg/mL · min for the sequence P → C (range, 1.91 to 5.01), which is not significantly different (P = .55). Of 45 assessable patients, there were five major responders (three complete responders and two partial responders). Four of five responses occurred at dosages above dose level 4 (P 175 mg/m2 + C 300 mg/m2). The median survival duration was best correlated with the P dose (4.8 months for doses <175 mg/m2 v 7.9 months for doses ≤ 175 mg/m2, P = .07; P-T ≤ 0.1 μmol/L, 4.8 months for <15 hours v 8.2 months for ≤ 15 hours, P = .06). Conclusion: There was no pharmacokinetic-sequence interaction between C and P in this study. A clear dose-response relation with respect to response rate and survival was observed. The pharmacokinetic parameter PT ≤ 0.1 μmol/L was related to improved survival in this study.

Original languageEnglish (US)
Pages (from-to)317-329
Number of pages13
JournalJournal of Clinical Oncology
Volume15
Issue number1
StatePublished - Jan 1997
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Huizing, M. T., Giaccone, G., van Warmerdam, L. J., Rosing, H., Bakker, P. J., Vermorken, J. B., Postmus, P. E., van Zandwijk, N., Koolen, M. G., ten Bokkel Huinink, W. W., van der Vijgh, W. J., Bierhorst, F. J., Lai, A., Dalesio, O., Pinedo, H. M., Veenhof, C. H., & Beijnen, J. H. (1997). Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. Journal of Clinical Oncology, 15(1), 317-329.