Preclinical toxicity studies included single and repeated administration of IDAMYCIN® at various dosage levels. These studies were conducted in vitro and in laboratory animals (mouse, rat, rabbit, dog). Patterns similar to those recommended for clinical use were employed, and doxorubicin was given by the same treatment schedule.
To ascertain the activity of the IDAMYCIN metabolite, idarubicinol, studies were conducted to determine its acute toxicity in the mouse, cardiotoxicity in the rat, and the potential to induce mutagenic effects.
Acute toxicology studies revealed average LD50 values of 4.3 mg/kg in the mouse and 2.8 mg/kg in the rat. In terms of mg/m≤, the LD50 values were about 18 mg/m≤ (mouse) and 17 mg/m≤ (rat). The lethal dose in dogs is estimated as 21 mg/m≤.
Gross pathology findings for the metabolite, idarubicinol, were similar to those described for IDAMYCIN. Pharmacotoxic signs and necropsy findings were consistent with the myelosuppression and gastrointestinal effects expected with a cytotoxic agent. These acute studies show that the hematolymphopoietic system and gastrointestinal tract are the primary targets, suggesting that IDAMYCIN has a preferential effect on actively proliferating tissues. Subchronic toxicity studies confirm this.
Subchronic toxicity studies indicate that the ma jor toxicity of IDAMYCIN is on the hematolymphopoietic system. IDAMYCIN appears to be about twice as myelotoxic as doxorubicin on a 3-day repeated dosing schedule. This indicates that IDAMYCIN should be tolerated clinically at least to the same extent as doxorubicin, taking into account the recommended clinical doses of 12 mg/m≤/3-day cycle for IDAMYCIN and 60 to 75 mg/m≤/3-day cycle for doxorubicin.
A study using female Sprague-Dawley rats was used to determine the carcinogenicity potential following a single dose of IDAMYCIN. Although this study does not constitute a full carcinogenicity bioassay, the results indicate that IDAMYCIN, like doxorubicin and daunorubicin, is carcinogenic after a single dose.
Other Toxicoligy Studies
A special study was performed to determine toxicity to the heart and kidneys of male rats given a single intravenous in jection of IDAMYCIN, idarubicinol, or doxorubicin.
IDAMYCIN was found to be cardiotoxic at Cl close 1.7-fold lower than doxorubicin. This finding is comparable to the relative cardiotoxicities of these two agents as estimated previously by the Bertozzoli mouse model and repeated dose toxicity studies Isee Subchronic Toxicity). This study also demonstrated that idarubicinol was about 1.6-fold less potent than IDAMYCIN for induction of cardiotoxicity. Slight-to-moderate renal lesions were observed in all treatment groups.
Organogenesis studies determined that at a dose 10.2 mg/kg/d) nontoxic to dams, IDAMYCIN® was clearly embryotoxic and teratogenic in rats, affecting 122/212 fetuses. The principal malformations included gross visceral changes and skeletal defects.
IDAMYCIN produced no teratogenic effects in rabbits even at the highest dose (0.1 mg/kg/dl nontoxic to dams. In previous studies, doxorubicin and daunorubicin were also found to be nonteratogenic in the rabbit while being embryotoxic and teratogenic in the rat.
The mutagenic potential of IDAMYCIN was tested in the Ames' Test, and preparations of S. cerevisiae D4, S. pombe P1, V79 Chinese hamster cells and human Iymphocytes. Mutagenicity was seen in all preparations except those involving S. pombe P1. As expected in a drug that interacts with DNA, IDAMYCIN has shown similar mutagenic potential in standard preclinical mutagenic tests as daunorubicin and doxorubicin in comparative studies.