TY - JOUR
T1 - Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients
T2 - A study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group
AU - Joerger, Markus
AU - Huitema, Alwin D.R.
AU - Richel, Dick J.
AU - Dittrich, Christian
AU - Pavlidis, Nikolas
AU - Briasoulis, Evangelos
AU - Vermorken, Jan B.
AU - Strocchi, Elena
AU - Martoni, Andrea
AU - Sorio, Roberto
AU - Sleeboom, Henk P.
AU - Izquierdo, Miguel A.
AU - Jodrell, Duncan I.
AU - Calvert, Hilary
AU - Boddy, Alan V.
AU - Hollema, Harry
AU - Féty, Regine
AU - Van Der Vijgh, Wjf J.F.
AU - Hempel, Georg
AU - Chatelut, Etienne
AU - Karlsson, Mats
AU - Wilkins, Justin
AU - Tranchand, Brigitte
AU - Schrijvers, Ad H.G.J.
AU - Twelves, Christian
AU - Beijnen, Jos H.
AU - Schellens, Jan H.M.
PY - 2007/11/1
Y1 - 2007/11/1
N2 - 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/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 tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10-4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
AB - 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/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 tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10-4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
UR - http://www.scopus.com/inward/record.url?scp=35948943122&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-0064
DO - 10.1158/1078-0432.CCR-07-0064
M3 - Article
C2 - 17975154
AN - SCOPUS:35948943122
SN - 1078-0432
VL - 13
SP - 6410
EP - 6418
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -