(Last updated: March 28, 2014; last reviewed: March 28, 2014)
Animal Carcinogenicity StudiesEmtricitabine 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 or in rats at doses up to 31 times the human systemic exposure at the therapeutic dose.1
Reproduction/FertilityNo effect of emtricitabine on reproduction or fertility was observed with doses that produced systemic drug exposures (as measured by area under the curve [AUC]) approximately 60-fold higher in female and male mice and 140-fold higher in male rats than observed with human exposure at the recommended therapeutic dose.1
Teratogenicity/Developmental ToxicityIncidence 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.1
Placental and Breast Milk PassageEmtricitabine 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.3 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 the mean ratio of cord blood/maternal emtricitabine concentrations was 1.17 ± 0.6 (n = 9).4 In a study of 15 women enrolled in IMPAACT P1026s who received emtricitabine during pregnancy, the mean cord to maternal blood ratio was 1.2 (90% CI, 1.0–1.5).5 In 8 women enrolled in PACTG 394 who were given a single dose of 600 mg emtricitabine with 900 mg of tenofovir, the median cord blood emtricitabine concentration was 717 ng/mL (range 21–1,072), and the median cord blood/maternal ratio was 0.85 (range, 0.46–1.07).6 Emtricitabine is excreted into human milk. In a study in the Ivory Coast, 5 HIV-infected women who chose to exclusively breastfeed their newborn infants were given 400 mg emtricitabine, 600 mg tenofovir, and 200 mg of nevirapine at onset of labor, followed by 200 mg of emtricitabine and 300 mg of tenofovir once daily for 7 days postpartum. The median minimal and maximal concentrations of emtricitabine in breast milk were 177 and 679 ng/mL, respectively (interquartile ranges 105–254 and 658–743 ng/mL, respectively), well above the estimated emtricitabine IC50 for HIV-1.7
Human Studies in PregnancyEmtricitabine pharmacokinetic (PK) parameters 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.4 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 the IMPAACT P1026s study, 26 women had emtricitabine PKs assessed during the third trimester (median 35 weeks) and 22 postpartum (mean 8 weeks postpartum).5 The PK parameters during pregnancy were slightly altered with respect to the postpartum period, with higher emtricitabine clearance (25.0 vs. 20.6 L/hour during pregnancy vs. postpartum, respectively) and lower 24-hour post-dose levels (0.058 vs. 0.085 mg/L), but the 24-hour, post-dose levels were well above the inhibitory concentration 50% (IC50) in all patients. Similar differences in PK parameters of emtricitabine among women during pregnancy or after delivery were found in the PACTG 394 study,6 and in a European study.8 Thus, these changes are not believed to be large enough to warrant dosage adjustment during pregnancy.