title: Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG.
abstract: 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.
authors.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. markus.joerger@kssg.ch
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Christian
authors.initials: C
authors.lastname: Dittrich
authors.forename: Nikolas
authors.initials: N
authors.lastname: Pavlidis
authors.forename: Evangelos
authors.initials: E
authors.lastname: Briasoulis
authors.forename: Jan B
authors.initials: JB
authors.lastname: Vermorken
authors.forename: Elena
authors.initials: E
authors.lastname: Strocchi
authors.forename: Andrea
authors.initials: A
authors.lastname: Martoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorio
authors.forename: Henk P
authors.initials: HP
authors.lastname: Sleeboom
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Izquierdo
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: Régine
authors.initials: R
authors.lastname: Féty
authors.forename: Ernst
authors.initials: E
authors.lastname: de Bruijn
authors.forename: Georg
authors.initials: G
authors.lastname: Hempel
authors.forename: Mats
authors.initials: M
authors.lastname: Karlsson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Tranchand
authors.forename: Ad H G J
authors.initials: AH
authors.lastname: Schrijvers
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004317:Doxorubicin; D003520:Cyclophosphamide