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Population pharmaco...
Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : a study by the EORTC-PAMM-NDDG
- Article/chapterEnglish2007
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LIBRIS-ID:oai:DiVA.org:uu-15120
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-15120URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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
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Huitema, Alwin D R
(author)
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Richel, Dick J
(author)
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Dittrich, Christian
(author)
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Pavlidis, Nikolas
(author)
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Briasoulis, Evangelos
(author)
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Vermorken, Jan B
(author)
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Strocchi, Elena
(author)
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Martoni, Andrea
(author)
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Sorio, Roberto
(author)
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Sleeboom, Henk P
(author)
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Izquierdo, Miguel A
(author)
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Jodrell, Duncan I
(author)
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Féty, Régine
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de Bruijn, Ernst
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Hempel, Georg
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Karlsson, MatsUppsala universitet,Institutionen för farmaceutisk biovetenskap(Swepub:uu)matskarl
(author)
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Tranchand, Brigitte
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Schrijvers, Ad H G J
(author)
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Twelves, Chris
(author)
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Beijnen, Jos H
(author)
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Schellens, Jan H M
(author)
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Uppsala universitetInstitutionen för farmaceutisk biovetenskap
(creator_code:org_t)
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In:Clinical Pharmacokinetics46:12, s. 1051-10680312-59631179-1926
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Joerger, Markus
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Huitema, Alwin D ...
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Richel, Dick J
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Dittrich, Christ ...
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Briasoulis, Evan ...
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Vermorken, Jan B
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Strocchi, Elena
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Martoni, Andrea
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Sorio, Roberto
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Sleeboom, Henk P
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Izquierdo, Migue ...
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Jodrell, Duncan ...
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Féty, Régine
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de Bruijn, Ernst
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Hempel, Georg
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Karlsson, Mats
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Tranchand, Brigi ...
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Schrijvers, Ad H ...
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Twelves, Chris
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Beijnen, Jos H
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Schellens, Jan H ...
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Uppsala University