Epirubicin. Clinical Pharmacology and Dose-effect Relationship

The pharmacokinetic properties of epirubicin are characterised by a triphasic plasma clearance, with half-lives for the initial (alpha), intermediate (beta) and terminal (gamma) elimination phases of approximately 3 minutes, 1 hour and 30 hours, respectively. These values are similar to or slightly shorter than the corresponding half-lives of doxorubicin. The total plasma clearance of epirubicin is approximately 50 L/h/m2, which is almost 2-fold higher than that of doxorubicin. This difference is mainly due to the relatively high volume of distribution of epirubicin, and the unique glucuronidation metabolic pathway of epirubicin and epirubicinol, which is not available to doxorubicin or doxorubicinol. Glucuronide metabolites of epirubicin and epirubicinol are not active per se, but could divert epirubicin from free radical formation, which may induce cardiotoxic effects. This may explain, at least in part, the lower cardiotoxicity of this new anthracycline relative to that of the parent compound. There is a linear relationship between the dose administered and area under the plasma concentration-time curve (AUC) values of both unchanged drug and metabolites, so that the total plasma clearance of epirubicin is constant with epirubicin doses ranging from 40 to 140 mg/m2. No variation in total plasma clearance as a function of age in the range of 31 to 74 years has been observed, and this parameter is unaffected by subsequent courses of treatment. Hepatic dysfunction causes an increase in the terminal elimination half-life of epirubicin, which is well correlated with serum bilirubin levels and which necessitates a reduction in epirubicin dosage. Epirubicin is responsible for a dose-dependent neutropenia, which is clearly related to drug exposure as established in pharmacodynamic studies. The maximum tolerated dose (MTD) of epirubicin was first established to be approximately 90 mg/m2 but this was re-examined recently and is now deemed to be approximately 150 mg/m2, which is about 2-fold higher than the MTD of doxorubicin. Cumulative cardiac toxicity occurs for both epirubicin and doxorubicin, but the dose ratio for equal risk is about 1.8 in favour of epirubicin (500 to 550 mg/m2 for doxorubicin vs 900 to 1000 mg/m2 for epirubicin). Consequently, there is not a higher risk of developing cardiotoxicity after administration of high dose epirubicin, since this adverse effect is associated with total cumulative anthracycline dose. In several controlled trials, epirubicin exhibited the same anticancer activity as doxorubicin when administered at equimolar doses to patients with advanced breast cancer.(ABSTRACT TRUNCATED AT 400 WORDS)