An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity.
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.
Prado
Carla M M
CM
Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.
Lima
Isac S F
IS
Baracos
Vickie E
VE
Bies
Robert R
RR
McCargar
Linda J
LJ
Reiman
Tony
T
Mackey
John R
JR
Kuzma
Michelle
M
Damaraju
Vijaya L
VL
Sawyer
Michael B
MB
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
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin