Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG (Journal article)
Joerger, M./ Huitema, A. D./ Richel, D. J./ Dittrich, C./ Pavlidis, N./ Briasoulis, E./ Vermorken, J. B./ Strocchi, E./ Martoni, A./ Sorio, R./ Sleeboom, H. P./ Izquierdo, M. A./ Jodrell, D. I./ Fety, R./ de Bruijn, E./ Hempel, G./ Karlsson, M./ Tranchand, B./ Schrijvers, A. H./ Twelves, C./ Beijnen, J. H./ Schellens, J. H.
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/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) 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 micromol . h/L [95% CI 889, 1001] vs 602 micromol . 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.
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής|
|Keywords:||Algorithms,Antibiotics, Antineoplastic/adverse effects/pharmacokinetics/therapeutic use,Antineoplastic Agents, Alkylating/adverse effects/pharmacokinetics/therapeutic,use,Area Under Curve,Breast Neoplasms/*drug therapy,Cyclophosphamide/adverse effects/*pharmacokinetics/therapeutic use,Doxorubicin/adverse effects/*pharmacokinetics/therapeutic use,Female,Hematologic Diseases/chemically induced,Humans,Middle Aged,Models, Biological,Treatment Outcome|
|Appears in Collections:||Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)|
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