Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: A study by the EORTC-PAMM-NDDG
Date
2007Author
Joerger, M.Huitema, A. D. R.
Richel, D. J.
Dittrich, C.
![ORCID logo](https://orcid.org/sites/default/files/images/orcid_16x16.png)
Briassoulis, E. Ch
Vermorken, J. B.
Strocchi, E.
Martoni, A.
Sorio, R.
Sleeboom, H. P.
Izquierdo, M. A.
Jodrell, D. I.
Féty, R.
Bruijn, E. De
Hempel, G.
Karlsson, M.
Tranchand, B.
Schrijvers, A. H. G. J.
Twelves, C.
Beijnen, J. H.
Schellens, J. H. M.
Source
Clinical pharmacokineticsVolume
46Issue
12Pages
1051-1068Google Scholar check
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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. © 2007 Adis Data Information BV. All rights reserved.
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