Pharmacology: Pharmacodynamics: Mechanism of Action: The mechanism of action of Pharmorubicin has not been fully elucidated but is probably related to its ability to bind DNA. Cell culture studies have shown cell penetration, localisation in the nucleus and inhibition of nucleic acid synthesis and mitosis. Pharmorubicin has proved to be active on the following experimental tumours: L 1210 ascites and P388 leukaemias, sarcoma SA 180 (solid and ascitic forms), melanoma B 16, mammary carcinoma, Lewis lung carcinoma and colon carcinoma 38.
The specificity of Pharmorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, bone marrow, gastrointestinal tract, lymphoid organs and the gonads are the main normal tissues damaged. Degenerative or functional alterations in liver and kidneys were also seen in animals dosed with Pharmorubicin.
Toxicity studies in animals have indicated that on a weight (mg per mg) basis Pharmorubicin has a better therapeutic index and less systemic and cardiac toxicity than doxorubicin.
Pharmorubicin is immunosuppressive in animals. Although there are no clinical data on the immunosuppressive effects of Pharmorubicin, effects similar to those seen with doxorubicin may be expected.
Clinical Trials: Early Breast Cancer: Data from 2 multicentre, randomised phase 3 studies support the use of Pharmorubicin 100 to 120 mg/m2 for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease (Stage II or III). In one study, an intensive cyclophosphamide/epirubicin/fluorouracil (CEF-120) regimen (epirubicin given in a dose of 60 mg/m2 on days 1 and 8) was compared with a conventional cyclophosphamide/methotrexate/fluorouracil (CMF) regimen. A total of 716 patients were randomised, 356 to CEF and 360 to CMF. Both disease free survival and overall survival were significantly prolonged in the CEF arm at five years. Disease free survival was 62% for CEF versus 53% for CMF (p=0.01) and overall survival was 77% for CEF versus 70% for CMF (p=0.043).
In the second study, 301 patients were randomised to receive tamoxifen 20 mg/day alone for 4 years and 303 patients were randomised to receive tamoxifen for 4 years in combination with epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks for 6 cycles. Although there was no significant difference between the two arms with regard to disease free survival and overall survival, there was a trend in favour of the combined use of epirubicin and tamoxifen. Disease free survival at two years was 85.1% versus 77.9% and at five years 70.4% versus 59.5% (p=0.07). Overall survival at two years was 93% versus 92% and at five years was 78.8% versus 72.9%.
Advanced Breast Cancer: Data from 4 open-label, multicentre, phase 3 studies support the use of Pharmorubicin for the treatment of patients with locally advanced or metastatic breast cancer. In Study 1, an intensified cyclophosphamide/epirubicin/fluorouracil (CEF-100) regimen (epirubicin given in a dose of 50 mg/m2 on days 1 and 8) was compared with a conventional CMF regimen (n=461). Studies 2 and 3 compared cyclophosphamide/epirubicin/fluorouracil regimens where only the dose of epirubicin varied. In both of these, epirubicin was given in a dose 50 mg/m2 on day 1 and compared with either 100 mg/m2 on day 1 (n=456) or 50 mg/m2 on days 1 and 8 (n=164). High dose epirubicin (135 mg/m2) was compared to conventional dose epirubicin (75 mg/m2) in Study 4 (n=151).
The efficacy endpoints included response rate (RR), duration of response (DR), time to tumour progression (TTP), time to treatment failure (TTF) and overall survival (OS). In Study 1, the CEF-100 regimen produced a significantly higher RR, a significantly longer TTP and a significantly longer TTF than the CMF regimen. In studies 2, 3 and 4, the higher dose epirubicin-containing regimens produced a significantly greater RR than the lower dose epirubicin-containing regimens. DR and TTF were also significantly longer in Study 3 and TTP was significantly longer in Study 4 for the higher dose epirubicin regimens.
Pharmacokinetics: There is evidence for a dose-response and dose-toxicity relationship for epirubicin in breast cancer, and to a lesser extent for lymphoma. This relationship is steeper and therefore more evident for doses of epirubicin above 90 mg/m2. Current data indicate that an increase in dose (for dose intensity) produces greater response rates.
Absorption/Distribution: When Pharmorubicin is administered intravesically, the systemic absorption is minimal. As with doxorubicin, Pharmorubicin may not be expected to cross the blood-brain barrier.
Elimination: In patients with normal hepatic and renal function, plasma levels after intravenous injection of 75-90 mg/m2 of the drug follow a triexponential decreasing pattern with a very fast first phase and a slow terminal phase with a mean half-life of about 40 hours. Plasma levels of the drug's main metabolite, the 13-OH derivative, are constantly somewhat lower and virtually parallel to those of the unchanged drug. Pharmorubicin is eliminated mainly through the liver; high plasma clearance values (0.9 L/min) indicate that the slow elimination of epirubicin is due to extensive tissue distribution. Urinary excretion accounts for approximately 11% of the administered dose in 48 hours. However, like doxorubicin, biliary excretion is likely to be the major excretion route. Impairment of liver function delays plasma clearance.
Toxicology: Preclinical safety data: Genotoxicity: Like most other antitumour and immunosuppressant agents, Pharmorubicin is mutagenic in animals (see Use in Pregnancy & Lactation).
Carcinogenicity: Pharmorubicin is carcinogenic in animals (see Use in Pregnancy & Lactation).