No developmental toxicity observed with dolutegravir in rat whole embryo culture

Abstract

Background An in vitro rat whole embryo culture study investigated whether direct exposure to dolutegravir (TivicayTM) 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.

Author reply to Copp et al. (2022) correspondence

“…Concerns about the article in EBioMedicine that Copp et al refers to (Mohan et al, 2021) have been published (Romach, Posobiec, Bloomer, Zamek-Gliszczynski, & Stanislaus, 2021), including small increases in NTDS only in the lower dose group but not in the higher dose group, using a combination of dolutegravir and other compounds which was formulated by crushing pills with no dose formulation analysis and no single agent controls. The conclusion made is contrary not only to the principles of teratology and establishing causality but also to the previous preclinical work (Stanislaus et al, 2019).To address the concerns that Copp et al has presented in the recent correspondence, first, the number of embryos used in the whole embryo culture study is typical for these types of studies; the rationale is discussed further in the article (Posobiec et al, 2021) and enhances the Stanislaus et al work. Second, as further discussed in Posobiec et al, the percentage of DTG in the embryo is approximately 6%, consistent with a DTG placental transfer study.…”

“…This author reply is in reference to the recent correspondence entitled “Dolutegravir and rat whole embryo culture” (Copp et al, 2022) regarding the article entitled “No developmental toxicity observed with dolutegravir in rat whole embryo culture” (Posobiec et al, 2021). Copp et al did not include updated data (Zash, 2019) from the clinical study in Botswana.…”

“…To address the concerns that Copp et al has presented in the recent correspondence, first, the number of embryos used in the whole embryo culture study is typical for these types of studies; the rationale is discussed further in the article (Posobiec et al, 2021) and enhances the Stanislaus et al work. Second, as further discussed in Posobiec et al, the percentage of DTG in the embryo is approximately 6%, consistent with a DTG placental transfer study.…”

Harmonization of criteria and terminology in fetal rat skeletal evaluations

“…Recommendations were made by the authors after reviewing the survey results, publications listed in this reference section and applying their combined expertise. The results of this survey were initially presented as posters at annual scientific meetings (Posobiec et al, 2021; Posobiec et al, 2022).…”

Dolutegravir and rat whole embryo culture

“…We were interested to read the recent paper by Posobiec et al (2021) in Birth Defects Research that reports a lack of teratogenicity using the anti-HIV drug, dolutegravir (DTG) in rat whole embryo culture. This is clinically important, as an elevated rate of neural tube defects (NTDs) was observed among women in Botswana taking a DTG-based regimen from conception (Zash et al, 2019;Zash, Makhema, & Shapiro, 2018).…”