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:7/31/2012; last reviewed:7/31/2012)
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 2.3% (21 of 899 births; 95% CI, 1.4%–3.5%) 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 excellent placental transfer in pregnant women. In 18 women who received 200 mg emtricitabine once 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 Similarly, in a study of 26 women in P1026s who received emtricitabine during pregnancy, the mean cord:maternal blood ratio was 1.2 (90% CI, 1.0–1.5).5 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 antiretroviral therapy including emtricitabine (200 mg once daily) at 30 to 36 weeks’ gestation and 6 to 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 non-pregnant 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 to 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 In the P1026s study, 26 women had emtricitabine PKs assessed during the third trimester (median 35 weeks) and 22 postpartum (mean 8 weeks postpartum).5 Comparing PKs during pregnancy with postpartum, higher emtricitabine clearance (25.0 vs. 20.6 liters/hour during pregnancy vs. postpartum, respectively) and lower 24-hour post-dose levels (0.058 vs. 0.085 mg/liter) were seen but the 24-hour post-dose levels were well above the inhibitory concentration 50% (IC50) in all patients. Thus, these changes are not believed to be large enough to warrant dosage adjustment during pregnancy.
References
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available at http://www.APRegistry.com.
- Szczech GM, Wang LH, Walsh JP, Rousseau FS. Reproductive toxicology profile of emtricitabine in mice and rabbits. Reprod Toxicol. Jan-Feb 2003;17(1):95-108. Available at http://www.ncbi.nlm.nih.gov/pubmed/12507664.
- 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. Mar 2009;53(3):1067-1073. Available at http://www.ncbi.nlm.nih.gov/pubmed/19104016.
- 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); February 3-8, 2008; Boston, MA. Abstract 629.
- Stek AM, Best BM, Luo W, et al. Effect of pregnancy on emtricitabine pharmacokinetics. HIV Med. Apr 2012;13(4):226-235. Available at http://www.ncbi.nlm.nih.gov/pubmed/22129166.