Published in:
01-12-2007 | Original Research Article
Population Pharmacokinetics and Pharmacodynamics of Doxorubicin and Cyclophosphamide in Breast Cancer Patients
A Study by the EORTC-PAMM-NDDG
Authors:
Dr Markus Joerger, Alwin D. R. Huitema, Dick J. Richel, Christian Dittrich, Nikolas Pavlidis, Evangelos Briasoulis, Jan B. Vermorken, Elena Strocchi, Andrea Martoni, Roberto Sorio, Henk P. Sleeboom, Miguel A. Izquierdo, Duncan I. Jodrell, Régine Féty, Ernst de Bruijn, Georg Hempel, Mats Karlsson, Brigitte Tranchand, Ad H. G. J. Schrijvers, Chris Twelves, Jos H. Beijnen, Jan H. M. Schellens
Published in:
Clinical Pharmacokinetics
|
Issue 12/2007
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Abstract
Aims
To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.
Patients and methods
Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m2 over 15 minutes followed by cyclophos-phamide 600 mg/m2 over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response.
Results
Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 μmol ∙ h/L [95% CI 889, 1001] vs 602 μmol ∙ h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance.
Conclusions
The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.