TY - JOUR
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
Y1 - 2007
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.
AB - 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.
KW - Breast cancer
KW - Cyclophosphamide, pharmacokinetics
KW - Doxorubicin, pharmacokinetics
KW - Pharmacokinetic modelling
KW - Population pharmacokinetics
UR - https://www.scopus.com/pages/publications/36249031853
U2 - 10.2165/00003088-200746120-00005
DO - 10.2165/00003088-200746120-00005
M3 - Article
C2 - 18027989
AN - SCOPUS:36249031853
SN - 0312-5963
VL - 46
SP - 1051
EP - 1068
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 12
ER -