(Last updated: March 28, 2014; last reviewed: March 28, 2014)
Animal Carcinogenicity StudiesEtravirine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests.1 Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200, and 400 mg/kg were administered to mice and doses of 70, 200, and 600 mg/kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted because of tolerability and reduced by 50% in mice and by 50% to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance to humans of these liver tumor findings in mice is unknown. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal versus human area under the curve ratios being 0.6-fold (mice) and 0.2- to 0.7-fold (rats).1
Reproduction/FertilityNo effect on fertility and early embryonic development was observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure equivalent to the recommended human dose (400 mg/day).1
Teratogenicity/Developmental ToxicityAnimal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the recommended human dose of 400 mg/day revealed no evidence of fetal toxicity or altered development. Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects (including malformations) were observed. In addition, no treatment effects were observed in a separate prenatal and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).1 In seven reported cases of etravirine use in pregnancy, no maternal, fetal, or neonatal toxicity was noted. One infant was born with a small accessory auricle on the right ear with no other malformations, but no birth defects were noted in the other children.2 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 PassageEtravirine concentrations in cord blood and maternal plasma at delivery were 112 ng/mL and 339 ng/mL, respectively (cord/maternal ratio of 33%), in one mother-infant pair.3 Placental passage of etravirine was described in a report of the use of etravirine, ritonavir-boosted darunavir, and enfuvirtide in a pregnant woman who gave birth to twins, with cord blood etravirine levels of 414 ng/mL in Twin 1 and 345 ng/mL in Twin 2 (no maternal delivery etravirine concentration reported).2 There are no data describing etravirine excretion in human breast milk.
Human Studies in PregnancyNo adequate and well-controlled studies of etravirine use in pregnant women have been conducted. Very limited case report data are available describing etravirine use in a total of 7 pregnant women.2 No adverse effects associated with etravirine use were reported. One report described etravirine pharmacokinetics (PK) in four pregnant women whose etravirine PK parameters were similar to those in non-pregnant adults.3