Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: A study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group

Markus Joerger*, Alwin D. R. Huitema, Dick J. Richel, Christian Dittrich, Nikolas Pavlidis, Evangelos Briasoulis, Jan B. Vermorken, Elena Strocchi, Andrea Martoni, Roberto Sorio, Henk P. Sleeboom, Miguel A. Izquierdo, Duncan I. Jodrell, Hilary Calvert, Alan V. Boddy, Harry Hollema, Regine Fety, Wjf J. F. Van der Vijgh, Georg Hempel, Etienne ChatelutMats Karlsson, Justin Wilkins, Brigitte Tranchand, Ad H. G. J. Schrijvers, Christian Twelves, Jos H. Beijnen, Jan H. M. Schellens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 mu mol/L (t(c > 0.05-0.2)) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients.

Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL(*)min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Serniphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data.

Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t(c > 0.05) was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel t(c > 0.05) > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t(c > 0.05) <61.4 h (89.0 versus 61.9 weeks; P = 0.05) Paclitaxel t(c > 0.05) was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C-max and area under the concentration-time curve) was the best predictor for thrombocytopenia (p <10(-4)).

Conclusions: In this group of patients, paclitaxel t(c > 0.05) is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Original languageEnglish
Pages (from-to)6410-6418
Number of pages9
JournalClinical Cancer Research
Volume13
Issue number21
DOIs
Publication statusPublished - 1-Nov-2007

Keywords

  • GYNECOLOGIC-ONCOLOGY-GROUP
  • PHASE-III
  • COMBINATION PACLITAXEL
  • RANDOMIZED-TRIAL
  • 3-HOUR INFUSION
  • BREAST-CANCER
  • TIME-COURSE
  • MODEL
  • CHEMOTHERAPY
  • CARCINOMA

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