lls in kidney, haemorrhage in gastro-intestinal tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible after 2 to 6 weeks without treatment.
Genotoxicity
The genotoxic potential of sunitinib was assessed in vitro and in vivo. Sunitinib was not mutagenic in bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro. Polyploidy (numerical chromosome aberrations) was observed in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo. The major active metabolite was not eva luated for genotoxic potential.
Carcinogenicity
The carcinogenic potential of sunitinib has been eva luated in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence of background haemangiosarcomas, and/or gastric mucosal hyperplasia have been observed at doses of 25 mg/kg/day following 1- or 6-months duration (7.3 times the AUC in patients administered the RDD). No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day (0.7 times the AUC in patients administered the RDD). The relevance of the carcinogenicity findings observed in the rasH2 transgenic mouse to humans following 1- and 6-months sunitinib treatment is unclear.
Reproductive and Developmental toxicity.
No effects on male or female fertility were observed in reproductive toxicity studies. However, in repeated-dose toxicity studies performed in rats and monkeys, effects on female fertility were observed in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus and decreased uterine and ovarian weights at clinically relevant systemic exposure levels. Effects on male fertility in rat were observed in the form of tubular atrophy in the testes, reduction of spermatozoa in epidydimis and colloid depletion in prostate and seminal vesicles at plasma exposure levels 18-fold higher than is observed in clinic.
In rats, embryo-foetal mortality was evident as significant reductions in the number of live foetuses, increased numbers of resorptions increased post-implantation loss, and total litter loss in 8 of 28 pregnant females at plasma exposure levels 5.5-fold higher than observed in clinic. In rabbits, reductions in gravid uterine weights and number of live foetuses were due to increases in the number of resorptions , increases in post-implantation loss and complete litter loss in 4 of 6 pregnant females at plasma exposure levels 3-fold higher than observed in clinic. Sunitinib treatment in rats during organogenesis resulted in developmental effects at 5 mg/kg/day consisting of increased incidence of foetal skeletal malformations, predominantly characterized as retarded ossification of thoracic/lumbar vertebrae and occurred at plasma exposure levels 6-fold higher than is observed in clinic. In rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels approximately equal to that observed in clinic, and cleft lip and cleft palate at plasma exposure levels 2.7-fold higher than observed in clinic.
6. PHARMACEUTICAL PARTICULARS
6.
