title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands. markus.joerger@kssg.ch
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Christian
authors.initials: C
authors.lastname: Dittrich
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pavlidis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Briasoulis
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: Elena
authors.initials: E
authors.lastname: Strocchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Martoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorio
authors.forename: Henk P
authors.initials: HP
authors.lastname: Sleeboom
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Izquierdo
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: Hilary
authors.initials: H
authors.lastname: Calvert
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Regine
authors.initials: R
authors.lastname: Féty
authors.forename: Wjf J F
authors.initials: WJ
authors.lastname: Van der Vijgh
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Mats
authors.initials: M
authors.lastname: Karlsson
authors.forename: Justin
authors.initials: J
authors.lastname: Wilkins
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tranchand
authors.forename: Ad H G J
authors.initials: AH
authors.lastname: Schrijvers
authors.forename: Christian
authors.initials: C
authors.lastname: Twelves
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel