Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Entry and Attachment Inhibitors

Fostemsavir (Rukobia, FTR)

Fostemsavir (FTR) is a prodrug of the active drug temsavir (TMR), a gp120-directed attachment inhibitor.

Summary

• Pharmacokinetic (PK) data are insufficient to make dosing recommendations for FTR during pregnancy.
• Clinical data are insufficient to characterize the risk for congenital anomalies associated with in utero exposure to FTR. No reproductive toxicity or teratogenicity concerns were identified in animal studies.

Human Studies in Pregnancy

Pharmacokinetics

No PK studies of FTR in pregnancy have been reported. A physiologically based PK model was developed to predict TMR PK in pregnant populations during each trimester to inform dosing. Simulations showed that TMR area under the curve in pregnant individuals decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment.¹

Placental and Breast Milk Passage

No data are available on placental or breast milk passage of FTR in humans.

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry (APR) provides updated birth defect data for FTR and other antiretroviral drugs twice a year through an interim report released in June and December. For the most recent data about FTR, refer to Table 5. Number of Birth Defects by Trimester of Earliest Exposure to Each Drug in the current APR interim report. Available data are limited and insufficient for drawing conclusions about the risk of birth defects among infants who were exposed to FTR. 

Animal Studies

Carcinogenicity

Temsavir was not genotoxic or mutagenic in vitro.²

Reproduction/Fertility

FTR did not adversely affect the fertility of male or female rats at TMR exposures approximately 10 times (males) and 186 times (females) higher than those achieved in humans at the recommended dose.²

Teratogenicity/Adverse Pregnancy Outcomes

No adverse embryo-fetal effects were observed in rats and rabbits at TMR exposures of approximately 180 times (rats) and 30 times (rabbits) the exposure in humans at the recommended dose. Maternal toxicity and increased embryonic death were observed in rabbits at TMR exposures approximately 60 times those in humans. In a rat study conducted at drug exposures approximately 200 times those in humans, fetal abnormalities (cleft palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue) and reductions in fetal body weights occurred in the presence of maternal toxicity.²

Placental and Breast Milk Passage

When FTR was administered to pregnant rats, FTR-related drug materials (e.g., TMR or metabolites) crossed the placenta and were detectable in fetal tissue. TMR is excreted in rat milk and was present at concentrations similar to those measured in maternal plasma on Day 11 postpartum.²

Excerpt From Table 14

References

1. Salem F, Nguyen D, Bush M, et al. Development of a physiologically based pharmacokinetic model of fostemsavir and its pivotal application to support dosing in pregnancy. CPT Pharmacometrics Syst Pharmacol. 2024;13(11):1881-1892. Available at: https://pubmed.ncbi.nlm.nih.gov/38690782.
2. Fostemsavir (Rukobia) [package insert]. Food and Drug Administration. 2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212950s004lbl.pdf.