Clinical Pharmacokinetics of Epirubicin

Abstract

Epirubicin (4'-epidoxorubicin) is a new anthracycline that has activity similar to doxorubicin (adriamycin) in a variety of solid neoplasms and haematologic malignancies. Importantly, epirubicin causes less cardiotoxicity than doxorubicin. There is extensive distribution of epirubicin into tissues and the elimination of the drug is predominantly biliary, with less than 15% of the drug excreted in the urine. The metabolism of epirubicin is characterised by complex biotransformation to relatively or totally inactive metabolites, including a 13-dihydro derivative, epirubicinol, 2 glucuronides and 4 aglycones. Quantitatively, the glucuronides of epirubicin and epirubicinol are very important, and this pathway, which is unique to epirubicin metabolism in humans, might explain the better tolerability of this drug compared with doxorubicin. Epirubicin pharmacokinetics may be described by a 3-compartment model, with median half-life values of 3.2 minutes, 1.2 and 32 hours for each phase. Total plasma clearance is 46 L/h/m2 and volume of distribution at steady-state is 1000 L/m2. The pharmacokinetics of epirubicin appears to be linear for doses up to the maximal tolerated dose of 150 to 180 mg/m2. Both intraperitoneal and intravesical administration of epirubicin are feasible, but remain of a rather restricted interest. The area under the plasma concentration-time curve of epirubicin is fairly well correlated with the relative kill of white blood cells. Therefore, epirubicin clearance can be used to predict haematological toxicity.

Quantitative liquid chromatographic analysis of anthracyclines in biological fluids

“…Lower limits of quantification (LLOQ) in the low ng/mL range (< 10 ng/mL) should guarantee detection up to 24 hours or more after administration. For the reduced metabolites, a similar LLOQ and an upper limit of quantification (ULOQ) of 250 ng/mL in plasma is advisable [6][7][8]73]. In addition to the determination of the LOQ (and LOD, limit of detection), the validation of analytical methods for the pharmacokinetic determination of anthracyclines in (pre)clinical studies requires that parameters such as precision and accuracy meet pre-set acceptance criteria and parameters such as selectivity, stability, linearity and recovery are evaluated [74][75][76].…”

“…After bolus administration, plasma anthracycline levels undergo a decay, which can generally be best fitted by a triexponential model, although also biexponential models -the intermediate phase not always being apparent-have been described [6][7][8]. Despite the fact that a considerable heterogeneity in the pharmacokinetic parameters of anthracyclines has been observed, both within and between studies, the plasma-concentration-time curve after short intravenous infusion can be roughly characterised by i) a rapid initial () distribution phase, lasting up to 1 hour, with half-lives in the range of minutes, ii) an intermediate () phase, with 4 half-lives in the range of a few hours, and iii) a much slower () terminal elimination phase, apparently established after 12 to 24 hours, with half-lives in the order of days [6,9].…”

Pharmacokinetic Drug Interactions with Anticancer Drugs

“…In addition, 493 readers are referred to recent reviews of the pharmacokinetics of doxorubicin (Cummings & Smyth 1988) and epirubicin (Robert 1994) for more information on these drugs.…”

Synthesis and cellular characterization of various nano-assemblies of cell penetrating peptide-epirubicin-polyglutamate conjugates for the enhancement of antitumor activity

“…Ineffective accumulation of drugs in tumors, lack of tumor specificity, heterogeneity of cancer cells, drug toxicity and drug resistance are factors that causes the lack of efficiency in cancer therapy [1,3,4]. Epirubicin (EPR) is an anthracycline drug that has been used alone or in combination with other drugs for treatment of various cancers such as breast, ovarian, gastric and lung [5,6].…”