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.
Pavlidis, Nicholas
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
Keyword(s):
Metadata
Show full item recordAbstract
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.
Collections
Cite as
Related items
Showing items related by title, author, creator and subject.
-
Article
«Juvenile» oncology - A missing subspecialty. The experience of a reference cancer centre
Pentheroudakis, George; Mauri, D.; Kostadima, Lida; Golfinopoulos, Vassilis; Alexiou, G.; Karakatsanis, A.; Pavlidis, Nicholas (2006)Introduction: Despite unique tumor epidemiology and a higher cancer incidence compared to pediatric patients, adolescents and young adults have not been receiving specialized, multidisciplinary, centralized care. In an ...
-
Article
Cancer of unknown primary site
Pavlidis, Nicholas; Pentheroudakis, George (2012)Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3-5 of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. ...
-
Article
Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Peccatori, Fedro A.; Azim, Hatem A.; Orecchia, R.; Hoekstra, H. J.; Pavlidis, Nicholas; Kesic, V.; Pentheroudakis, George (2013)