(Last updated: March 28, 2014; last reviewed: March 28, 2014)
Animal Carcinogenicity StudiesFosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Carcinogenicity studies of fosamprenavir showed an increase in the incidence of hepatocellular adenomas and hepatocellular carcinomas at all doses tested in male mice and at the highest dose tested in female mice. In rats, the incidence of hepatocellular adenomas and thyroid follicular cell adenomas in males (all doses tested) and in females (two highest doses tested) was also increased. Repeat dose studies in rats produced effects consistent with enzyme activation, which predisposes rats, but not humans, to thyroid neoplasms. In rats only, there was an increase in interstitial cell hyperplasia at higher doses and an increase in uterine endometrial adenocarcinoma at the highest dose tested. The incidence of endometrial findings was slightly increased over concurrent controls but was within background range for female rats. Thus the relevance of the uterine endometrial adenocarcinomas is uncertain. Exposures in the carcinogenicity studies were 0.3- to 0.7-fold (mice) and 0.7- to 1.4-fold (rats) those in humans given 1400 mg twice daily of fosamprenavir alone, and 0.2- to 0.3-fold (mice) and 0.3- to 0.7-fold (rats) those in humans given 1400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily or 0.1- to 0.3-fold (mice) and 0.3- to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily.
Reproduction/FertilityNo impairment of fertility or mating was seen in rats at doses providing 3 to 4 times the human exposure to fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. No effect was seen on the development or maturation of sperm in rats at these doses.
Teratogenicity/Developmental ToxicityFosamprenavir was studied in rabbits at 0.8 and in rats at 2 times the exposure in humans to fosamprenavir alone and at 0.3 (rabbits) and 0.7 (rats) times the exposure in humans to the combination of fosamprenavir and ritonavir. In rabbits administered fosamprenavir (alone or in combination) the incidence of abortion was increased. In contrast, administration of amprenavir at a lower dose in rabbits was associated with abortions and an increased incidence of minor skeletal variations from deficient ossification of the femur, humerus, and trochlea. Fosamprenavir administered to pregnant rats (at 2 times human exposure) was associated with a reduction in pup survival and body weights in rats. F1 female rats had an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights compared to controls. The number of first-trimester exposures to fosamprenavir that have been monitored to date in the Antiretroviral Pregnancy Registry is insufficient to allow conclusions to be drawn regarding risk of birth defects.1
Placental and Breast Milk PassageIn a small study of women receiving fosamprenavir during pregnancy, the median (range) amprenavir concentration in cord blood was 0.27 (0.09–0.60) ug/mL and the median (range) ratio of amprenavir concentration in cord blood to that in maternal plasma at the time of delivery was 0.24 (0.06–0.93).2 A second small study in pregnancy yielded a similar mean ratio (95% CI) of amprenavir concentration in cord blood to that in maternal plasma at the time of delivery of 0.27 (0.24, 0.30).3 Amprenavir is excreted in the milk of lactating rats; it is not known if it is excreted in human milk.
Human Studies in PregnancyData on fosamprenavir in pregnant women are very limited. Fosamprenavir pharmacokinetic data have been reported in 26 women during pregnancy and postpartum. Following standard dosing with fosamprenavir 700 mg and ritonavir 100 mg, fosamprenavir area under the curve and 12-hour trough concentration were somewhat lower during pregnancy and higher postpartum compared to historical data. Fosamprenavir exposure during pregnancy appeared to be adequate for patients without protease inhibitor resistance mutations.2 A pediatric liquid formulation is approved for children older than age 2 years, but no dosing information is available for neonates.