Authors: Joerger, Markus; Huitema, Alwin D.R.¹; Richel, Dick J.²; Dittrich, Christian³; Pavlidis, Nikolas⁴; Briasoulis, Evangelos⁴; Vermorken, Jan B.⁵; Strocchi, Elena⁶; Martoni, Andrea⁷; Sorio, Roberto⁸; Sleeboom, Henk P.⁹; Izquierdo, Miguel A.¹⁰; Jodrell, Duncan I.¹¹; Féty, Régine¹²; Ernst de Bruijn,¹³; Hempel, Georg¹⁴; Karlsson, Mats¹⁵; Tranchand, Brigitte; Schrijvers, Ad H.G.J.¹⁶; Twelves, Chris¹⁷; Beijnen, Jos H.; Schellens, Jan H.M.

Source: Clinical Pharmacokinetics, Volume 46, Number 12, 2007 , pp. 1051-1068(18)

Publisher: Adis International

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 cyclophosphamide 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.

Keywords: Breast cancer; Cyclophosphamide; Doxorubicin; Pharmacokinetic modelling; Population pharmacokinetics

Document Type: Research article

Affiliations: 1: 1 Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/ Slotervaart Hospital, Amsterdam, The Netherlands 2: 3 Medical Spectrum Twente, Enschede, The Netherlands 3: 4 Ludwig Boltzmann Institute for Applied Cancer Research (LBI-ACR VIEnna) and  Applied Cancer Research-Institute for Translational Research (ACR-ITR VIEnna),  Kaiser-Franz-Josef Hospital, Vienna, Austria 4: 5 Ioannina University Hospital, Ioannina, Greece 5: 6 University Hospital Antwerp, Edegem, Belgium 6: 7 University of Bologna, Bologna, Italy 7: 8 Policlinico S. Orsola-Malpighi, Bologna, Italy 8: 9 National Cancer Institute, Aviano, Italy 9: 10 Leyenburg Hospital, Den Haag, The Netherlands 10: 11 Catalan Institute of Oncology, Barcelona, Spain 11: 12 University of Edinburgh, Edinburgh, United Kingdom 12: 13 Centre R. Gauducheau, Saint Herblain, France 13: 14 UZ Gasthuisberg, Leuven, Belgium 14: 15 University of Münster, Münster, Germany 15: 16 Uppsala University, Uppsala, Sweden 16: 20 European Organisation for Research and Treatment of Cancer-New Drug Development  Group, Brussels, Belgium 17: 21 University of Leeds, Bradford NHS Trust & Beatson Oncology Centre, Glasgow,  United Kingdom

Publication date: 2007-01-01

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• In this Subject: Pharmacology
• By this author: Joerger, Markus ;  Huitema, Alwin D.R. ;  Richel, Dick J. ;  Dittrich, Christian ;  Pavlidis, Nikolas ;  Briasoulis, Evangelos ;  Vermorken, Jan B. ;  Strocchi, Elena ;  Martoni, Andrea ;  Sorio, Roberto ;  Sleeboom, Henk P. ;  Izquierdo, Miguel A. ;  Jodrell, Duncan I. ;  Féty, Régine ;  Ernst de Bruijn, ;  Hempel, Georg ;  Karlsson, Mats ;  Tranchand, Brigitte ;  Schrijvers, Ad H.G.J. ;  Twelves, Chris ;  Beijnen, Jos H. ;  Schellens, Jan H.M.

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