Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation.
OBJECTIVE
An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose.


METHODS
The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutropenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression.


RESULTS
There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) for epirubicin correlated with prothrombin index (P < .01), antipyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, some of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined.


CONCLUSIONS
These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.
Department of Medical Oncology and Palliative Care, Westmead Hospital, Australia. howardg@westmed.wh.usyd.edu.au
H P
HP
Gurney
S
S
Ackland
V
V
Gebski
G
G
Farrell
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000983:Antipyrine; D001647:Bile Acids and Salts / Q000097:blood; D001830:Body Surface Area; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000903:Antibiotics, Antineoplastic; D001647:Bile Acids and Salts; D015251:Epirubicin; D000983:Antipyrine