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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

Authors' Affiliations: ¹ Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute; ² Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute; ³ Free University Medical Center, Amsterdam, the Netherlands; ⁴ Medical Spectrum Twente, Enschede, the Netherlands; ⁵ LBI-ACR VIEnna and ACR-ITR VIEnna, KFJ-Spital, Vienna, Austria; ⁶ Ioannina University Hospital, Ioannina, Greece; ⁷ University Hospital Antwerp, Edegem, Belgium; ⁸ Universita di Bologna; ⁹ Policlinico S. Orsola-Malpighi, Bologna, Italy; ¹⁰ National Cancer Institute, Aviano, Italy; ¹¹ Leyenburg Hospital, Den Haag, the Netherlands; ¹² Catalan Institute of Oncology, Barcelona, Spain; ¹³ University of Edinburgh, Edinburgh, United Kingdom; ¹⁴ Newcastle University, Newcastle upon Tyne, United Kingdom; ¹⁵ University Medical Center, Groningen, the Netherlands; ¹⁶ Centre R Gauducheau, Saint Herblain, France; ¹⁷ University of Münster, Münster, Germany; ¹⁸ Centre Claudius Regaud, Toulouse, France; ¹⁹ Uppsala University, Uppsala, Sweden; ²⁰ Ctr Leon Berard; ²¹ Lyon University, Lyon, France; ²² EA3738, CTO, Faculty of Medicine Lyon Sud, Oullins, France; ²³ European Organization for Research and Treatment of Cancer-New Drug Development Group, Brussels, Belgium; ²⁴ University of Leeds, Bradford NHS Trust and Beatson Oncology Centre, Glasgow, United Kingdom; and ²⁵ Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

Requests for reprints: Markus Joerger, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-205129111; Fax: 31-204443920; E-mail: markus.joerger{at}kssg.ch.

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 µmol/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/m²) 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.

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				M. J. Egorin Population Pharmacokinetc/Pharmacodynamic Modeling of Paclitaxel and Carboplatin in Ovarian Cancer Clin. Cancer Res., April 15, 2008; 14(8): 2517 - 2517. [Full Text] [PDF]