Population Pharmacokinetics and Pharmacodynamics of Doxorubicin and Cyclophosphamide in Breast Cancer Patients : A Study by the EORTC-PAMM-NDDG

• Published in: Clinical pharmacokinetics Vol. 46; no. 12; pp. 1051 - 1068
• Main Authors: JOERGER, Markus, HUITEMA, Alwin D. R, SLEEBOOM, Henk P, IZQUIERDO, Miguel A, JODRELL, Duncan I, FETY, Régine, DE BRUIJN, Ernst, HEMPEL, Georg, KARLSSON, Mats, TRANCHAND, Brigitte, SCHRIJVERS, Ad H. G. J, TWELVES, Chris, RICHEL, Dick J, BEIJNEN, Jos H, SCHELLENS, Jan H. M, DITTRICH, Christian, PAVLIDIS, Nikolas, BRIASOULIS, Evangelos, VERMORKEN, Jan B, STROCCHI, Elena, MARTONI, Andréa, SORIO, Roberto
• Format: Journal Article
• Language: English
• Published: Auckland Adis international 01-01-2007; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Algorithms; Antibiotics, Antineoplastic - adverse effects; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Area Under Curve; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Cyclophosphamide; Cyclophosphamide - adverse effects; Cyclophosphamide - pharmacokinetics; Cyclophosphamide - therapeutic use; Doxorubicin; Doxorubicin - adverse effects; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; FARMACI; Female; Gynecology. Andrology. Obstetrics; Hematologic Diseases - chemically induced; Humans; Mammary gland diseases; Medical sciences; Middle Aged; Models, Biological; Pharmacokinetic modelling; PHARMACY; Population pharmacokinetics; Treatment Outcome; Tumors; Europe; Antineoplastic agent; Human; DNA topoisomerase (ATP-hydrolysing); Population pharmacokinetics; Enzyme; Enzyme inhibitor; Breast cancer; Topoisomerase II inhibitor; Malignant tumor; Doxorubicin; Biological activity; Mammary gland diseases; Alkylating agent; Oxazaphosphinane derivatives; Antibiotic; Cyclophosphamide; Isomerases; Nitrogen mustard; Anthracyclins; Woman; Cancer; European Organization for Research and Treatment of Cancer
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.2165/00003088-200746120-00005

To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients.
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.
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.
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.