Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Protease Inhibitors
Darunavir (Prezista, DRV)
(Last updated:9/14/2011)
Darunavir (Prezista, DRV) is classified as FDA pregnancy category C.
Animal carcinogenicity studies
Darunavir 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 AUC) were between 0.4- and 0.7-fold (mice) and 0.7-and 1-fold (rats) of those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).
Reproduction/fertility
No effects on fertility and early embryonic development were seen with darunavir in rats.
Teratogenicity/developmental toxicity
No 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 pre- 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–1,000 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 (CYP450) liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. Sexual development, fertility, and mating performance of offspring were not affected by maternal treatment. No data are available in humans.
Placental and breast milk passage
No animal studies of placental passage of darunavir have been reported. As noted above, passage of darunavir into breast milk has been noted in rats. It is unknown if placental or breast milk passage of darunavir occurs in humans.
Human studies in pregnancy
Currently, very limited data exist about darunavir in pregnancy [1-7]. Reports conflict about whether darunavir has low or moderate placental transfer [6-7]. Generally, PIs have a low degree of placental transfer. Darunavir is not recommended for children younger than 3 years of age. Darunavir is one of the study drugs in the ongoing International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1026: “Pharmacokinetic Study of Anti-HIV Drugs During Pregnancy.” Few pregnancy exposures have been reported to the Antiretroviral Pregnancy Registry; therefore, no conclusions can be made about risk of birth defects.
References
1. Jaworsky D, Thompson C, Yudin MH, et al. Use of newer antiretroviral agents, darunavir and etravirine with or without raltegravir, in pregnancy: a report of two cases. Antivir Ther. 2010;15(4):677-680.
2. Ivanovic J, Bellagamba R, Nicastri E, et al. Use of darunavir/ritonavir once daily in treatment-naive pregnant woman: pharmacokinetics, compartmental exposure, efficacy and safety. AIDS. 2010 Apr 24;24(7):1083-1084.
3. Pacanowski J, Bollens D, Poirier JM, et al. Efficacy of darunavir despite low plasma trough levels during late pregnancy in an HIV-hepatitis C virus-infected patient. AIDS. 2009 Sep 10;23(14):1923-1924.
4. Furco A, Gosrani B, Nicholas S, et al. Successful use of darunavir, etravirine, enfuvirtide and tenofovir/emtricitabine in pregnant woman with multiclass HIV resistance. AIDS. 2009 Jan 28;23(3):434-435.
5. Sued O, Lattner J, Gun A, et al. Use of darunavir and enfuvirtide in a pregnant woman. Int J STD AIDS. 2008 Dec;19(12):866-867.
6. Pinnetti C, Tamburrini E, Ragazzoni E, De Luca A, Navarra P. Decreased plasma levels of darunavir/ritonavir in a vertically infected pregnant woman carrying multiclass-resistant HIV type-1. Antivir Ther. 2010;15(1):127-129.
7. Ripamonti D, Cattaneo D, Cortinovis M, Maggiolo F, Suter F. Transplacental passage of ritonavir-boosted darunavir in two pregnant women. Int J STD AIDS. 2009 Mar;20(3):215-216.