Ellence (Epirubicin Hydrochloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated.

Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms.

Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors.

PHARMACOKINETICS

Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m² and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6- to 10-minute, single-dose intravenous infusions of epirubicin at doses of 60 to 150 mg/m² in patients with solid tumors are shown in Table 1. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.

Distribution.    Following intravenous administration, epirubicin is rapidly and widely distributed into the tissues. Binding of epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma.

Metabolism.    Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified:

1. reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol;
2. conjugation of both the unchanged drug and epirubicinol with glucuronic acid; (3) loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites.

Excretion.    Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found about 60% of the total radioactive dose in feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose were recovered as epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after treatment.

PHARMACOKINETICS IN SPECIAL POPULATIONS

Age.    A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed that age affects plasma clearance of epirubicin in female patients. The predicted plasma clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of 25 years of age. An insufficient number of males > 50 years of age were included in the study to draw conclusions about age-related alterations in clearance in males. Although a lower epirubicin starting dose does not appear necessary in elderly female patients, and was not used in clinical trials, particular care should be taken in monitoring toxicity when epirubicin is administered to female patients > 70 years of age. (See PRECAUTIONS).

Gender.    In patients </= 50 years of age, mean clearance values in adult male and female patients were similar. The clearance of epirubicin is decreased in elderly women (see Pharmacokinetics in Special Populations - Age).

Pediatric.    The pharmacokinetics of epirubicin in pediatric patients have not been evaluated.

Race.    The influence of race on the pharmacokinetics of epirubicin has not been evaluated.

Hepatic Impairment.    Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and were given epirubicin doses of 12.5 to 90 mg/m². Patients in Group 2 had alterations in both serum AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an epirubicin dose of 25 mg/m²(n=8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received epirubicin doses of 12.5 to 120 mg/m². The median plasma clearance of epirubicin was decreased compared to patients with normal hepatic function by about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic impairment have not been evaluated. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

Renal Impairment.    No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine >/= 5 mg/dL (see WARNINGS and DOSAGE AND ADMINISTRATION). Patients on dialysis have not been studied.

DRUG-DRUG INTERACTIONS

Taxanes.    Coadministration of paclitaxel or docetaxel did not affect the pharmacokinetics of epirubicin when given immediately following the taxane.

Cimetidine.    Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy) increased the mean AUC of epirubicin (100 mg/m²) by 50% and decreased its plasma clearance by 30% (see PRECAUTIONS).

Drugs metabolized by cytochrome P-450 enzymes. No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition or induction by epirubicin of oxidative cytochrome P-450 isoenzymes.

CLINICAL STUDIES

Two randomized, open-label, multicenter studies evaluated the use of ELLENCE Injection 100 to 120 mg/m² in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axiliary-node-positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m² of epirubicin per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an epirubicin-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m² of epirubicin per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have >/= 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 2 shows the treatment regimens that the patients received.

In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had >/= 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had >/= 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study.

The efficacy endpoints of relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results for endpoints are described in terms of the outcomes at 5 years. In Study MA-5, epirubicin-containing combination therapy (CEF-120) showed significantly longer 5-year RFS than CMF (62% versus 53%; stratified log rank p=0.013). The overall reduction in risk of relapse was 24%. The 5-year OS was also greater for the epirubicin-containing CEF-120 regimen than for the CMF regimen (77% versus 70%; stratified log rank p=0.043; nonstratified log rank p=0.13). The overall relative reduction in the risk of death was 29%.

In Study GFEA-05, patients treated with the higher-dose epirubicin regimen (FEC-100) had a significantly longer 5-year RFS (65% versus 52%, log rank p=0.007) and OS (76% versus 65%, log rank p=0.007) than patients given the lower dose regimen (FEC-50). The overall reduction in risk of relapse was 32%. The relative reduction in the risk of death was 31%.

Although the trials were not powered for subset analyses, improvement in RFS and OS were observed both in patients with 1-3 nodes positive and in those with >/= 4 nodes positive for tumor involvement when comparing the CEF-120 or FEC-100 groups with the control groups. In addition, in the GFEA-05 study, similar improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50. Efficacy results for the two studies are shown in Table 3.

The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 1 and 2 and those for Study GFEA-05 are shown in Figures 3 and 4.