Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients

A study by the EORTC-PAMM-NDDG

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 & 2 others Jos H. Beijnen, Jan H M Schellens

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1051-1068
Number of pages18
JournalClinical Pharmacokinetics
Volume46
Issue number12
Publication statusPublished - 2007

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Doxorubicin
Cyclophosphamide
Pharmacokinetics
Breast Neoplasms
Population
Area Under Curve
Neutrophils
Pentostatin
Pharmaceutical Preparations
Body Surface Area
Carbamazepine
Creatinine
Prospective Studies
Therapeutics

Keywords

  • Breast cancer
  • Cyclophosphamide, pharmacokinetics
  • Doxorubicin, pharmacokinetics
  • Pharmacokinetic modelling
  • Population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Joerger, M., Huitema, A. D. R., Richel, D. J., Dittrich, C., Pavlidis, N., Briasoulis, E., ... Schellens, J. H. M. (2007). Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: A study by the EORTC-PAMM-NDDG. Clinical Pharmacokinetics, 46(12), 1051-1068.

Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : A study by the EORTC-PAMM-NDDG. / 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; De Bruijn, Ernst; Hempel, Georg; Karlsson, Mats; Tranchand, Brigitte; Schrijvers, Ad H G J; Twelves, Chris; Beijnen, Jos H.; Schellens, Jan H M.

In: Clinical Pharmacokinetics, Vol. 46, No. 12, 2007, p. 1051-1068.

Research output: Contribution to journalArticle

Joerger, M, Huitema, ADR, Richel, DJ, Dittrich, C, Pavlidis, N, Briasoulis, E, Vermorken, JB, Strocchi, E, Martoni, A, Sorio, R, Sleeboom, HP, Izquierdo, MA, Jodrell, DI, Féty, R, De Bruijn, E, Hempel, G, Karlsson, M, Tranchand, B, Schrijvers, AHGJ, Twelves, C, Beijnen, JH & Schellens, JHM 2007, 'Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: A study by the EORTC-PAMM-NDDG', Clinical Pharmacokinetics, vol. 46, no. 12, pp. 1051-1068.
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 ; De Bruijn, Ernst ; Hempel, Georg ; Karlsson, Mats ; Tranchand, Brigitte ; Schrijvers, Ad H G J ; Twelves, Chris ; Beijnen, Jos H. ; Schellens, Jan H M. / Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : A study by the EORTC-PAMM-NDDG. In: Clinical Pharmacokinetics. 2007 ; Vol. 46, No. 12. pp. 1051-1068.
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T1 - Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients

T2 - A study by the EORTC-PAMM-NDDG

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 - Féty, Régine

AU - De Bruijn, Ernst

AU - Hempel, Georg

AU - Karlsson, Mats

AU - Tranchand, Brigitte

AU - Schrijvers, Ad H G J

AU - Twelves, Chris

AU - Beijnen, Jos H.

AU - Schellens, Jan H M

PY - 2007

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N2 - 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.

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KW - Breast cancer

KW - Cyclophosphamide, pharmacokinetics

KW - Doxorubicin, pharmacokinetics

KW - Pharmacokinetic modelling

KW - Population pharmacokinetics

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