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.
AIMS: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancerpatients. 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.
Authors: L J Ayash; J E Wright; O Tretyakov; R Gonin; A Elias; C Wheeler; J P Eder; A Rosowsky; K Antman; E Frei Journal: J Clin Oncol Date: 1992-06 Impact factor: 44.544
Authors: T L Chen; M J Kennedy; L W Anderson; S B Kiraly; K C Black; O M Colvin; L B Grochow Journal: Drug Metab Dispos Date: 1997-05 Impact factor: 3.922
Authors: Roy E Smith; Stewart J Anderson; Ann Brown; Aaron P Scholnik; Ajit M Desai; Carl G Kardinal; Barry C Lembersky; Eleftherios P Mamounas Journal: Clin Breast Cancer Date: 2002-12 Impact factor: 3.225
Authors: Jonás Samuel Pérez-Blanco; Dolores Santos-Buelga; María Del Mar Fernández de Gatta; Jesús María Hernández-Rivas; Alejandro Martín; María José García Journal: Br J Clin Pharmacol Date: 2016-09-06 Impact factor: 4.335
Authors: Shuang Liang; Richard C Brundage; Pamala A Jacobson; Anne Blaes; Mark N Kirstein Journal: Br J Clin Pharmacol Date: 2016-06-03 Impact factor: 4.335
Authors: Jeannine S McCune; David H Salinger; Paolo Vicini; Celeste Oglesby; David K Blough; Julie R Park Journal: J Clin Pharmacol Date: 2008-10-16 Impact factor: 3.126
Authors: Olivia Campagne; Bo Zhong; Sreenath Nair; Tong Lin; Jie Huang; Arzu Onar-Thomas; Giles Robinson; Amar Gajjar; Clinton F Stewart Journal: Clin Cancer Res Date: 2019-12-03 Impact factor: 12.531
Authors: Vanessa Gonzalez-Covarrubias; Jianping Zhang; James L Kalabus; Mary V Relling; Javier G Blanco Journal: Drug Metab Dispos Date: 2008-11-20 Impact factor: 3.922