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

Joerger, M. et al. (2007) 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. Clinical Cancer Research, 13(21), pp. 6410-6418.

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 micromol/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. Semiphysiologic 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: UNSPECIFIED
• Authors: Joerger, M., Huitema, A.D.R., Richel, D.J., Dittrich, C., Pavlidis, N., Briasoulis, E., Vermorken, J.B., Strocchi, E., Martoni, A., Sorio, R., Sleeboom, H.P., Izquierdo, M.A., Jodrell, D.I., Calvert, H., Boddy, A.V., Hollema, H., Fety, R., Van der Vijgh, W.J.F., Hempel, G., Chatelut, E., Karlsson, M., and Wilk,
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Clinical Cancer Research