Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG.
OBJECTIVE
To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.


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.
Joerger
Markus
M
Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. markus.joerger@kssg.ch
Huitema
Alwin D R
AD
Richel
Dick J
DJ
Dittrich
Christian
C
Pavlidis
Nikolas
N
Briasoulis
Evangelos
E
Vermorken
Jan B
JB
Strocchi
Elena
E
Martoni
Andrea
A
Sorio
Roberto
R
Sleeboom
Henk P
HP
Izquierdo
Miguel A
MA
Jodrell
Duncan I
DI
Féty
Régine
R
de Bruijn
Ernst
E
Hempel
Georg
G
Karlsson
Mats
M
Tranchand
Brigitte
B
Schrijvers
Ad H G J
AH
Twelves
Chris
C
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000465:Algorithms; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004317:Doxorubicin; D003520:Cyclophosphamide