No developmental toxicity observed with dolutegravir in rat whole embryo culture.

Background: An in vitro rat whole embryo culture study investigated whether direct exposure to dolutegravir (Tivicay ) during the critical period for neural tube development would result in abnormal development.

Methods: Dolutegravir (DTG), and HIV integrase inhibitor, was administered at 0 (vehicle), 5.3 μg/mL and 9.3 μg/mL on Gestation Day (GD) 9 through 11 (approximate 40 hour exposure period) along with positive (Valproic Acid) and negative (Penicillin G) controls. The DTG concentrations tested were selected based on clinical exposure at the maximum human recommended dose and maximum feasible concentration that could be formulated under the experimental conditions.

Results: Approximately 6% of DTG present in the culture media was absorbed into the embryos, demonstrating embryonic exposure at a similar level to that observed in a rat DTG placental transfer study. There was no effect in either the DTG or Penicillin G groups on visceral yolk sac size/morphology, embryo size, somite number and embryo morphology at any concentration tested. Valproic Acid, by contrast, produced statistically significant decreases in visceral yolk sac size, embryo size and somite number along with defects in visceral yolk sac and embryonic morphology, including neural tube defects (NTDs), in all embryos.

Conclusion: DTG at the maximum human recommended dose administered to rats in a whole embryo culture assay did not produce any abnormal effects, while the positive control Valproic Acid produced abnormal effects, including neural tube defects.