(Last updated: March 28, 2014; last reviewed: March 28, 2014)
Animal Carcinogenicity StudiesRitonavir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Carcinogenicity studies in mice and rats have been completed. In male mice, a dose-dependent increase in adenomas of the liver and combined adenomas and carcinomas of the liver was observed at levels of 50, 100, or 200 mg/kg/day; based on area under the curve, exposure in male mice at the highest dose was approximately 0.3-fold that in male humans at the recommended therapeutic dose. No carcinogenic effects were observed in female mice with exposures 0.6-fold that of female humans at the recommended therapeutic dose. No carcinogenic effects were observed in rats at exposures up to 6% of recommended therapeutic human exposure.
Reproduction/FertilityNo effect of ritonavir has been seen on reproductive performance or fertility in rats at drug exposures 40% (male) and 60% (female) of that achieved with human therapeutic dosing; higher doses were not feasible because of hepatic toxicity in the rodents.
Teratogenicity/Developmental ToxicityNo ritonavir-related teratogenicity has been observed in rats or rabbits. Developmental toxicity, including early resorptions, decreased body weight, ossification delays, and developmental variations such as wavy ribs and enlarged fontanelles, was observed in rats; however, these effects occurred only at maternally toxic dosages (exposure equivalent to 30% of human therapeutic exposure). In addition, a slight increase in cryptorchidism was also noted in rats at exposures equivalent to 22% of the human therapeutic dose. In rabbits, developmental toxicity (resorptions, decreased litter size, and decreased fetal weight) was observed only at maternally toxic doses (1.8 times human therapeutic exposure based on body surface area).
Placental and Breast Milk TransferTransplacental passage of ritonavir has been observed in rats with fetal tissue-to-maternal-serum ratios >1.0 at 24 hours post-dose in mid- and late-gestation fetuses. In a human placental perfusion model, the clearance index of ritonavir was very low, with little accumulation in the fetal compartment and no accumulation in placental tissue.2 In a Phase I study of pregnant women and their infants (PACTG 354, see below), transplacental passage of ritonavir was minimal.3 In addition, in a study of cord blood samples from six women treated with ritonavir during pregnancy, the cord blood concentration was less than the assay limit of detection in 83% and was only 0.38 µg/mL in the remaining woman.4 In contrast, in a study of plasma and hair drug concentration in 51 mother-infant pairs in Uganda receiving ritonavir-boosted-lopinavir-based therapy during pregnancy and breastfeeding, infant plasma levels at delivery and hair levels at age 12 weeks suggested in utero transfer of ritonavir: 2% of infants had detectable plasma ritonavir concentrations at birth and mean infant-to-maternal-hair concentrations at 12 weeks postpartum was 0.47 for ritonavir.5 However, transfer during breastfeeding was not observed, with no infant having detectable ritonavir plasma levels at 12 weeks.
Human Studies in PregnancyA Phase I/II safety and pharmacokinetic study (PACTG 354) of ritonavir (500 or 600 mg twice daily) in combination with zidovudine and lamivudine in pregnant HIV-infected women and their infants showed lower levels of ritonavir during pregnancy than postpartum.3 Ritonavir concentrations are also reduced during pregnancy versus postpartum when the drug is used at a low dose (100 mg) to boost the concentrations of other protease inhibitors.6,7