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
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Emtricitabine (Emtriva, FTC)
(Last updated:9/14/2011)
Emtricitabine (Emtriva, FTC) is classified as FDA pregnancy category B.
Animal carcinogenicity studies
Emtricitabine was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 26 times the human systemic exposure at a therapeutic dose of 200 mg/day or in rats at doses up to 31 times the human systemic exposure at the therapeutic dose.
Reproduction/fertility
No effect of emtricitabine on reproduction or fertility was observed with doses that produced systemic drug exposures (as measured by AUC) approximately 60-fold higher in female mice and 140-fold higher in male mice than observed with human exposure at the recommended therapeutic dose.
Teratogenicity/developmental toxicity
Incidence of fetal variations and malformations was not increased with emtricitabine dosing in mice that resulted in systemic drug exposure 60-fold higher than observed with human exposure at recommended doses or in rabbits with dosing resulting in drug exposure 120-fold higher than human exposure.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to emtricitabine in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with emtricitabine. Among cases of first-trimester emtricitabine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.7% (17 of 641 births; 95% CI, 1.7%–4.8%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance [1].
Placental and breast milk passage
Emtricitabine has been shown to cross the placenta in mice and rabbits; the average fetal/maternal drug concentration was 0.4 in mice and 0.5 in rabbits [2]. Emtricitabine has been shown to have good placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine daily during pregnancy, mean cord blood concentration was 300 ± 268 ng/mL and mean ratios of cord blood/maternal emtricitabine concentrations were 1.17 ± 0.6 (n = 9) [3]. When 35 women were administered 400 mg of emtricitabine in combination with tenofovir at delivery, median maternal and cord concentrations were 1.02 (0.034–2.04) and 0.74 (0.0005–1.46) mg/L, respectively [4]. It is unknown if emtricitabine is excreted in human milk.
Human studies in pregnancy
Emtricitabine PKs have been evaluated in 18 HIV-infected pregnant women receiving combination antiretroviral therapy (ART) including emtricitabine (200 mg once daily) at 30–36 weeks gestation and 6–12 weeks postpartum [3]. Emtricitabine exposure was modestly lower during the third trimester (8.6 µg*h/mL [5.2–15.9]) compared with the postpartum period (9.8 µg*h/mL [7.4–30.3]). Two-thirds (12 of 18) of pregnant women versus 100% (14 of 14) of postpartum women met the AUC target (10th percentile in nonpregnant adults). Trough emtricitabine levels were also lower during pregnancy (minimum plasma concentration [Cmin] 52 ng/mL [14–180]) compared with the postpartum period (86 ng/mL [<10–306]). In another study of 35 women who received 400 mg of emtricitabine with tenofovir at delivery, median population AUC, maximum plasma concentration (Cmax), and Cmin were 14.3 µg*h/mL, 1,680 ng/mL, and 76 ng/mL, respectively [4]. Currently, data are insufficient to recommend a dosage adjustment during pregnancy.
References
1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2011. Wilmington, NC: Registry Coordinating Center; 2010. Available from URL: http://www.APRegistry.com. 2011.
2. Szczech GM, Wang LH, Walsh JP, Rousseau FS. Reproductive toxicology profile of emtricitabine in mice and rabbits. Reprod Toxicol. 2003 Jan-Feb;17(1):95-108.
3. Hirt D, Urien S, Rey E, et al. Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2009 Mar;53(3):1067-1073.
4. Best B, Stek A, Hu C, et al. High-dose lopinavir and standard-dose emtricitabine pharmacokinetics during pregnancy and postpartum. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); Feb 3-8, 2008; Boston, MA.