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
Integrase Inhibitors
Raltegravir (Isentress)
(Last updated:9/14/2011)
Raltegravir (Isentress) is classified as FDA 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 1,000 mg/kg/day. In a case report of use in late pregnancy, the raltegravir cord blood-to-maternal blood ratio at delivery was 1.06 [1]. 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.
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 nonpregnant individuals; thus the standard dose appears appropriate in pregnancy [2]. Raltegravir readily crossed the placenta; in 6 deliveries with evaluation, the ratio of cord blood to maternal plasma was 0.98 (95% confidence interval [CI], 0.09–2.26). In a separate report, 3 pregnant women with multiresistant HIV-1 were given raltegravir in late pregnancy to rapidly reduce maternal viral load [3]. Raltegravir concentrations within 3 hours of delivery in the neonates of 2 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. However, no adverse reactions were observed in mothers or infants. Whether raltegravir is secreted in human milk is unknown.
References
1. 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. 2010 Sep;65(9):2050-2052.
2. Best BM, Capparelli EV, Stek A, et al. Raltegravir pharmacokinetics during pregnancy. Paper presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); Sep. 12-15, 2010; Boston, MA.
3. McKeown DA, Rosenvinge M, Donaghy S, et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. AIDS. 2010 Sep 24;24(15):2416-2418.