Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG
2007 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 46, no 12, 1051-1068 p.Article in journal (Refereed) Published
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 mu mol . h/L [95% CI 889, 1001] vs 602 mu mol . 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
Place, publisher, year, edition, pages
2007. Vol. 46, no 12, 1051-1068 p.
Breast cancer, Cyclophosphamide, Doxorubicin, Pharmacokinetic modelling, Population pharmacokinetics
IdentifiersURN: urn:nbn:se:uu:diva-15120ISI: 000251704300004PubMedID: 18027989OAI: oai:DiVA.org:uu-15120DiVA: diva2:42891