(Last updated:March 28, 2014; last reviewed:March 28, 2014)
Animal Carcinogenicity StudiesDarunavir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas was observed in both male and female mice and rats as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on area under the curve) were between 0.4- and 0.7-fold (mice) and 0.7-and 1-fold (rats) those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg/day).
Reproduction/FertilityNo effects on fertility and early embryonic development were seen with darunavir in rats.
Teratogenicity/Developmental ToxicityNo embryotoxicity or teratogenicity was seen in mice, rats, or rabbits. Because of limited bioavailability of darunavir in animals and dosing limitation, the plasma exposures were approximately 50% (mice and rats) and 5% (rabbits) of those obtained in humans. In the rat prenatal and postnatal development study, a reduction in pup weight gain was observed with darunavir alone or with ritonavir exposure via breast milk during lactation. In juvenile rats, single doses of darunavir (20 mg/kg–160 mg/kg at ages 5–11 days) or multiple doses of darunavir (40 mg/kg–1000 mg/kg at age 12 days) caused mortality. The deaths were associated with convulsions in some of the animals. Within this age range, exposures in plasma, liver, and brain were dose- and age-dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the cytochrome P450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. Sexual development, fertility, or mating performance of offspring was not affected by maternal treatment. Fewer than 200 first-trimester pregnancy exposures have been reported to the Antiretroviral Pregnancy Registry; therefore, no conclusions can be made about risk of birth defects.
Placental and Breast Milk PassageNo animal studies of placental passage of darunavir have been reported. Although variable transplacental transfer of darunavir has been observed in some case reports, in a study of 14 mother/infant pairs, the median (range) ratio of darunavir concentration in cord blood to that in maternal delivery plasma was 24% (6%–58%).1,2,3,4,5 Passage of darunavir into breast milk has been noted in rats; whether breast milk passage of darunavir occurs in humans is unknown.
Human Studies in PregnancyCurrently, limited data exist about darunavir in pregnancy.1-11 Three intensive pharmacokinetic studies of darunavir/ritonavir administered as 600 mg/100 mg twice a day or 800 mg/100 mg once a day during pregnancy demonstrate 17% to 35% reductions in darunavir plasma concentration during the third trimester compared with postpartum.1,5,11 Because of low trough levels with once-daily dosing, twice-daily dosing of darunavir is recommended during pregnancy. A study of use of an increased twice-daily darunavir dose during pregnancy is under way. Darunavir plasma protein binding decreases during pregnancy, which increases the unbound plasma darunavir fraction and may partially mitigate the decrease in total darunavir concentration.11