Pharmacologic rationale for intravesicalN-Trifluoroacetyladriamycin-14-valerate (AD 32): a preclinical study

Summary

Based on previous clinical findings following systemic administration, as well as appropriate laboratory evidence, the novel lipophilic anthracycline analogueN-Trifluoroacetyladriamycin-14-valerate (AD 32) has been identified as an agent of potential value in the intravesical therapy of superficial bladder carcinoma. Toward this end, using a rat model, the present study was designed to evaluate the potential for toxicity of a therapeutic dose of AD 32 given intravesically. With regard to systemic toxicity, following a single intravesical dose of AD 32 (20 mg/kg), the total systemic drug exposure (0–6 h), expressed as the area under the plasma concentration-time curve, was 14.2 μg min ml⁻¹, or <1% of the corresponding value obtained when the identical dose was injected intravenously (2,392 μg min ml⁻¹). In separate studies, a single intravenous dose of AD 32 (20 mg/kg) given to normal animals produced only a 20% reduction in white blood cell counts as compared with a 60% reduction following the administration of a therapeutic dose of Adriamycin (5 mg/kg); no effect was seen for either drug on red blood cell production. Taken together, these results imply that systemic drug exposure following the intravesical instillation of a therapeutic dose of AD 32 would result in negligible (∼0.2%) hematotoxic potential. Furthermore, intravesical instillation of AD 32 (20 mg/kg) at a concentration (10 mg/ml) greater than that projected for use in humans resulted in no evidence of contact toxicity to the rat bladder urothelium. Thus, based on experimental and clinical considerations of safety and efficacy, AD 32 appears to be an excellent candidate for the intravesical treatment of superficial bladder cancer.