title: An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity.
abstract: OBJECTIVE
  Although body composition has emerged as an important predictor of drug efficacy and toxicity, explanations for this association are unclear. Our goal was to investigate relationships between lean body mass (LBM), liver size/function and epirubicin pharmacokinetics (PK) and toxicity.
  
  
  METHODS
  Data from a clinical study (n = 24) of patients with breast cancer receiving adjuvant intravenous FE(100)C chemotherapy were used to examine relationships between LBM, liver size, and epirubicin clearance. Muscle tissue and liver mass were measured by analysis of computerized tomography cross-sectional images, and an extrapolation of muscle mass to total LBM compartment was employed. Population PK analysis of epirubicin was undertaken to test effects of body composition on epirubicin clearance and area under the curve (AUC).
  
  
  RESULTS
  Estimated LBM was extremely variable in this cohort ranging from 32.9 to 67.3 kg. LBM was associated with neutrophil nadir (r = 0.5, P = 0.023), and mean LBM was lower for patients presenting with toxicity compared to those where toxicity was absent (41.6 vs. 56.2 kg, P = 0.002); 33% of variance in clearance was explained by LBM and aspartate aminotransferase (AST). Liver mass was not related to epirubicin clearance likely due to larger livers presenting with larger fat content, but liver attenuation (degree of fat infiltration) and AST were associated with AUC.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to examine relationships between LBM, liver mass/function and epirubicin PK and toxicity. This exploratory work investigates the notion of organs and tissues having distinctive contributions to the distribution and metabolism of antineoplastic drugs.
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
authors.forename: Carla M M
authors.initials: CM
authors.lastname: Prado
authors.forename: Isac S F
authors.initials: IS
authors.lastname: Lima
authors.forename: Vickie E
authors.initials: VE
authors.lastname: Baracos
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Linda J
authors.initials: LJ
authors.lastname: McCargar
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Michelle
authors.initials: M
authors.lastname: Kuzma
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Damaraju
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sawyer
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D001823:Body Composition; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008111:Liver Function Tests; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D009929:Organ Size; D011446:Prospective Studies; D014057:Tomography, X-Ray Computed
chemical_list: D000903:Antibiotics, Antineoplastic; D015251:Epirubicin