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
(Last updated:7/31/2012; last reviewed:7/31/2012)
Raltegravir (Isentress) is classified as Food and Drug Administration Pregnancy Category C.
Animal carcinogenicity studies
Raltegravir was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term animal carcinogenicity studies of raltegravir are ongoing.
Reproduction/fertility animal studies
Raltegravir produced no adverse effects on fertility of male or female rats at doses up to 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended adult human dose).
Teratogenicity/developmental toxicity animal studies
Studies in rats and rabbits revealed no evidence of treatment-related effects on embryonic/fetal survival or fetal weights from raltegravir administered in doses producing systemic exposures approximately 3- to 4-fold higher than the exposure at the recommended adult human daily dose. In rabbits, no treatment-related external, visceral, or skeletal changes were observed. However, treatment-related increases in the incidence of supernumerary ribs were seen in rats given raltegravir at 600 mg/kg/day (providing exposures 3-fold higher than the exposure at the recommended human daily dose).
Placental and breast milk passage
Placental transfer of raltegravir was demonstrated in both rats and rabbits. In rats given a maternal dose of 600 mg/kg/day, mean fetal blood concentrations were approximately 1.5- to 2.5-fold higher than in maternal plasma at 1 and 24 hours post-dose, respectively. However, in rabbits, the mean drug concentrations in fetal plasma were approximately 2% of the mean maternal plasma concentration at both 1 and 24 hours following a maternal dose of 1000 mg/kg/day. In humans, raltegravir appears to readily cross the placenta. In P1026s, maternal and cord blood from six deliveries of mothers receiving raltegravir-based therapy during pregnancy were evaluated; the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval, 0.09–2.26).1 Other case reports have shown similarly high cord blood/maternal blood drug level ratios of 1.00 to 1.06.2,3 In a report of three pregnant women with multiresistant HIV-1 who were given raltegravir in late pregnancy to rapidly reduce maternal viral load, raltegravir concentrations within 3 hours of delivery in the neonates of two patients were approximately 7 and 9.5 times higher than in the mother’s paired sample; in the third infant, maternal plasma was not available but neonatal concentration was still high 2.5 hours after delivery.4 However, no adverse reactions were observed in mothers or infants. Raltegravir is secreted in the milk of lactating rats, with mean drug concentrations in milk about 3-fold higher than in maternal plasma at a maternal dose of 600 mg/kg/day. No effects in rat offspring were attributable to raltegravir exposure through breast milk. Whether raltegravir is secreted in human milk is unknown.
Human studies in pregnancy
Only limited data exist on the use of raltegravir in pregnancy. Raltegravir pharmacokinetics (PKs) were evaluated in 10 women in the IMPAACT P1026s study. Raltegravir PKs showed extensive variability but did not appear to be consistently altered during the third trimester compared with postpartum and historical data in non-pregnant individuals; thus the standard dose appears appropriate in pregnancy.1 In a case series of 5 pregnant women treated with raltegravir in combination with 2 or 3 other ARV drugs because of persistent viremia or late presentation, the drug was well tolerated and led to rapid reduction in HIV RNA levels.5 Drug levels were not measured in that study.
- Best BM, Capparelli EV, Stek A, et al. Raltegravir pharmacokinetics during pregnancy. Paper presented at: 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2010; Boston, MA.
- Pinnetti C, Baroncelli S, Villani P, et al. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy. J Antimicrob Chemother. Sep 2010;65(9):2050-2052. Available at http://www.ncbi.nlm.nih.gov/pubmed/20630894.
- Croci L, Trezzi M, Allegri MP, et al. Pharmacokinetic and safety of raltegravir in pregnancy. Eur J Clin Pharmacol. Mar 1 2012. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382989.
- McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. AIDS. Sep 24 2010;24(15):2416-2418. Available at http://www.ncbi.nlm.nih.gov/pubmed/20827058.
- Taylor N, Touzeau V, Geit M, et al. Raltegravir in pregnancy: a case series presentation. Int J STD AIDS. Jun 2011;22(6):358-360. Available at http://www.ncbi.nlm.nih.gov/pubmed/21680678.