Mechanism of Action

Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G₂. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.

Pharmacokinetics after Intravesical Administration of ValstarÔ

When 800 mg ValstarÔ was administered intravesically to patients with carcinoma in situ, ValstarÔ penetrated into the bladder wall. The mean total anthracycline concentration measured in bladder tissue exceeded the levels causing 90% cytoxicity to human bladder cells cultured in vitro. During the two-hour dose-retention period, the metabolism of ValstarÔ to its major metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol was neglible. After retention, the drug was almost completely excreted by voiding the instillate. Mean percent recovery of ValstarÔ, N-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from six patients was 98.6%, 0.4%, and 99.0% of the total administered drug, respectively. During the two-hour dose-retention period, only nanogram quantities of ValstarÔ were absorbed into the plasma. Valrubicin metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood.

Total systemic exposure to anthracyclines during and after intravesical administration of ValstarÔ is dependent upon the condition of the bladder wall. The mean AUC_{0-6 hours} (total anthracyclines exposure) for an intravesical dose of 900 mg of ValstarÔ administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/L•hr. In patients receiving 800 mg of ValstarÔ 5 to 51 minutes after typical (n=8) and extensive (n=5) transurethral resection of bladder tumors (TURBs), the mean AUC_{0-6 hours} values for total anthracyclines were 409 and 788 nmol/L•hr, respectively. The AUC_{0-6 hours} total exposure to anthracyclines was 18,382 nmol/L•hr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of ValstarÔ. Administration of a comparable intravenous dose of ValstarÔ (600 mg/m²; n=2) as a 24-hour infusion resulted in an AUC_{0-6 hours} for total anthracyclines of 11,975 nmol/L•hr. These results are shown in FIGURE 2.

FIGURE 2. Comparison of Mean AUC_{0-6 hours} in Valstar^TM Clinical Studies (N=number of patients)

The patient with a perforated bladder who received 800 mg of ValstarÔ intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration. Systemic hematologic toxicity from ValstarÔ was not seen after an intravesical dose of 800 mg of ValstarÔ unless perforation of the urinary bladder occurred.

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