Mechanism of Action
Cerubidine has antimitotic and cytotoxic activity through a number of proposed mechanisms of action. Cerubidine forms complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand DNA breaks result.
Cerubidine may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA.
Cerubidine possesses an antitumor effect against a wide spectrum of animal tumors, either grafted or spontaneous.
Following intravenous injection of Cerubidine, plasma levels of daunorubicin decline rapidly, indicating rapid tissue uptake and concentration. Thereafter, plasma levels decline slowly with a half-life of 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after drug administration, the predominant plasma species is daunorubicinol, an active metabolite, which disappears with a half-life of 26.7 hours.
Cerubidine is rapidly and widely distributed in tissues, with highest levels in the spleen, kidneys, liver, lungs, and heart. The drug binds to many cellular components, particularly nucleic acids. There is no evidence that Cerubidine crosses the blood-brain barrier, but the drug apparently crosses the placenta.
Metabolism and Elimination
Cerubidine is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of daunorubicin. Further metabolism via reduction cleavage of the glycosidic bond, 4-O demethylation, and conjugation with both sulfate and glucuronide have been demonstrated. Simple glycosidic cleavage of daunorubicin or daunorubicinol is not a significant metabolic pathway in man. Twenty-five percent of an administered dose of Cerubidine is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.
Although appropriate studies with Cerubidine have not been performed in the pediatric population, cardiotoxicity may be more frequent and occur at lower cumulative doses in children.
Although appropriate studies with Cerubidine have not been performed in the geriatric population, cardiotoxicity may be more frequent in the elderly. Caution should also be used in patients who have inadequate bone marrow reserves due to old age. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving Cerubidine.
Renal and Hepatic Impairment
Doses of Cerubidine should be reduced in patients with hepatic and renal impairment. Patients with serum bilirubin concentrations of 1.2 to 3 mg/dL should receive 75% of the usual daily dose and patients with serum bilirubin concentrations greater than 3 mg/dL should receive 50% of the usual daily dose. Patients with serum creatinine concentrations of greater than 3 mg/dL should receive 50% of the usual daily dose. (See WARNINGS, Evaluation of Hepatic and Renal Function).
In the treatment of adult acute nonlymphocytic leukemia, Cerubidine, used as a single agent, has produced complete remission rates of 40 to 50%, and in combination with cytarabine, has produced complete remission rates of 53 to 65%.
The addition of Cerubidine to the two-drug induction regimen of vincristine-prednisone in the treatment of childhood acute lymphocytic leukemia does not increase the rate of complete remission. In children receiving identical CNS prophylaxis and maintenance therapy (without consolidation), there is prolongation of complete remission duration (statistically significant, p<0.02) in those children induced with the three drug (Cerubidine-vincristine-prednisone) regimen as compared to two drugs. There is no evidence of any impact of Cerubidine on the duration of complete remission when a consolidation (intensification) phase is employed as part of a total treatment program.
In adult acute lymphocytic leukemia, in contrast to childhood acute lymphocytic leukemia, Cerubidine during induction significantly increases the rate of complete remission, but not remission duration, compared to that obtained with vincristine, prednisone, and L-asparaginase alone. The use of Cerubidine in combination with vincristine, prednisone, and L-asparaginase has produced complete remission rates of 83% in contrast to a 47% remission in patients not receiving Cerubidine.