The Nonclinical Safety Evaluation of the Anticancer Drug Atragen® (Liposomal All-Trans-Retinoic Acid)

Autor: Chris W. Wilson, Thomas L. Wallace, Paul A. Cossum, Scott A. Bazemore, Jeffrey L. Larson
Rok vydání: 2000
Předmět:
Zdroj: International Journal of Toxicology. 19:33-42
ISSN: 1092-874X
1091-5818
DOI: 10.1080/109158100225024
Popis: ATRAGEN® is a liposome-encapsulated intravenous (IV) formulation of the anticancer drug all- trans-retinoic acid (tretinoin). Retinoids as a class of compounds produce a characteristic profile of toxicities collectively known as hypervitaminosis A. As part of the nonclinical regulatory submission, it was important to determine if liposome encapsulation of tretinoin would change the expected profile of toxicities. To this end, a single-dose study in rats and repeated-dose 28-day studies in rats and dogs were conducted. In the single-dose study, ATRAGEN was given as a single IV bolus via the tail vein at dosages of 5, 20, or 80 mg/kg. In the first repeated-dose studies in rats, ATRAGEN was given by tail vein infusion at dosages of 2.5, 15, or 25 mg/kg/day and in the second, at dosages of 1, 10 or 10 mg/kg/day. The second study in rats also included a group given free tretinoin at a dose of 10 mg/kg/day; lowered to 1 mg/kg/day. ATRAGEN was given to dogs as an IV infusion in the cephalic or saphenous vein at dosages of 2.5, 5, or 10 mg/kg/day. ATRAGEN was not acutely toxic in rats at doses of 5 or 20 mg/kg, whereas deaths were seen at 80 mg/kg. In contrast, free tretinoin at a dosage of 10 mg/kg caused the deaths of most male rats after the first dose in the repeated-dose study; consequently, the dose was lowered to 1 mg/kg/day for remaining males and all females in that study. In the 28-day repeated-dose studies, minimal toxicities were observed in either rats or dogs at ATRAGEN doses of 2.5 mg/kg/day or less. Both free tretinoin and ATRAGEN at 1 mg/kg/day were without signs of hypervitaminosis A in rats. Moderate to marked retinoid-associated hypervitaminosis A was observed in the 28-day rats studies in the dose range of 10 to 25 mg/kg/day. In dogs, repeated administration of ATRAGEN of 5 or 10 mg/kg/day also led to moderate to marked hypervitaminosis A. In both species, hypervitaminosis A was manifested primarily as bone and testicular toxicities. In bone, premature closure of epiphyseal growth plates and/or a decrease in the activity of cells in the growth plate were seen. Loss of the cartilaginous growth plate and replacement with less dense trabecular bone resulted in weakened bones, most evident in rats. Rats had increased levels of serum alkaline phosphatase (ALP) and bone fractures were common with ATRAGEN doses of 10 mg/kg/day and higher. In addition to effects on bone growth, endosteal fibroplasia, exostosis, and periosteal hemorrhages were observed in dogs. In both species, diffuse testicular atrophy, degenerative spermatic elements, and loss of seminiferous epithelium in the epididymis were observed microscopically. Hepatic enzyme levels were increased in rats, but no histopathological correlate was identified. Moderate to moderately severe nephrosis exemplified by a loss and/or degeneration of the kidney tubules was seen in dogs given 5 or 10 mg/kg/day. There was an increased weight of the spleens in rats receiving high dose volumes of liposomes; that is, control rats receiving empty liposomes and in rats receiving ATRAGEN in large dose volumes to provide tretinoin at dosages of 10 mg/kg/day and greater. Microscopically, there was an accumulation of macrophages with prominent vacuoles in the spleens of these rats. This effect on the spleen was not considered a pathological process but a clearance of liposomal material from the circulation by phagocytosis. No other toxicities were observed. Thus, these nonclinical safety studies of ATRAGEN conducted in rats or dogs found no unique toxicities from those observed previously in laboratory animals given tretinoin or other retinoids.
Databáze: OpenAIRE
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