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.
OBJECTIVE
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.


METHODS
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.
Joerger
Markus
M
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. markus.joerger@kssg.ch
Huitema
Alwin D R
AD
Richel
Dick J
DJ
Dittrich
Christian
C
Pavlidis
Nikolas
N
Briasoulis
Evangelos
E
Vermorken
Jan B
JB
Strocchi
Elena
E
Martoni
Andrea
A
Sorio
Roberto
R
Sleeboom
Henk P
HP
Izquierdo
Miguel A
MA
Jodrell
Duncan I
DI
Calvert
Hilary
H
Boddy
Alan V
AV
Hollema
Harry
H
Féty
Regine
R
Van der Vijgh
Wjf J F
WJ
Hempel
Georg
G
Chatelut
Etienne
E
Karlsson
Mats
M
Wilkins
Justin
J
Tranchand
Brigitte
B
Schrijvers
Ad H G J
AH
Twelves
Christian
C
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D016190:Carboplatin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018450:Disease Progression; D015195:Drug Design; D005060:Europe; D005260:Female; D006801:Humans; D007700:Kinetics; D009503:Neutropenia; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011237:Predictive Value of Tests; D013921:Thrombocytopenia; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel