Abstract
Doses of cytotoxic drugs are routinely adjusted according to body surface area. We have evaluated this practice in 32 women with advanced breast cancer treated with single-agent epirubicin 12.5-120 mg m(-2). Epirubicin and its metabolites were measured by high-performance liquid chromatography (HPLC). Unadjusted plasma clearance was calculated from dose in mg, and adjusted clearance from dose in mg m(-2). Unadjusted clearance did not correlate with surface area, height, weight, per cent ideal body weight or body mass index. There was no difference in the coefficient of variation (CV) of adjusted and unadjusted clearance (39.4% and 37.7% respectively). The AUC that would have resulted from giving an unadjusted dose was calculated. This predicted AUC was accurate, unbiased and had the same CV as the actual AUC. Similarly, in 11 patients an analysis of actual and predicted neutropenia confirmed that unadjusted dosing would have had no significant effect on the pattern of myelosuppression. Normalization of epirubicin dosage according to surface area appears not to reduce either pharmacokinetic or pharmacodynamic variability.
Highlights
This paper addresses the foliowing questions in relation to epirubicin dose modifications: (1) do physical characteristics influence the arinability in epirubicin pharmacokinetics: (2) does adjustment of dose according to surface area appear to reduce this variability: (3) what would be the effect on epirubicin pharmacokinetics and pharmacodynamics of abandoning surface area dose normalization?
Impact of surface area dose adjustment on pharmacokinetics (AUC). These findings suggest there is no pharmacokinetic basis for modifying epirubicin dose according to surface area
The most important finding in this paper is that there is no relationship between total plasma clearance of epirubicin and any clinical or biochemical parameter or physical characteristic, including body surface area
Summary
The study was approved by the local ethics committee and all patients gave written informed consent. Epirubicin pharmacokinetics were studied in 32 women with advanced breast cancer who had received no prior anthracycline treatment. Pharmacokinetics were studied during their first cycle of chemotherapy. All patients had normal liver biochemistry with serum aspartate aminotransferase (AST) and serum bilirubin levels within the normal reference range for the hospital laboratory. Normal serum alkaline phosphatase (ALP) levels were not required as many patients had radiological evidence of bone metastases. Creatinine clearance was estimated using the formula of Lott and Hayton ( 1980)
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