# In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $777,388

## Abstract

Title: In vivo evaluation of safety and pharmacology of a sustained release formulation of dolutegravir in pre-
conception and early stages of pregnancy
Abstract:
Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent an important alternative to improve
adherence to HIV/AIDS treatment and prevention. Dolutegravir (DTG) is a highly effective ARV drug with low
toxicity, improved tolerability, better drug–drug interaction profile, low side-effects, and high genetic barrier to
resistance. Due to its excellent properties, dolutegravir became widely used as part of ARV therapies for HIV.
Recently, we used dolutegravir for development of an ultra-LA, removable system that delivers drug for up to 9
months and can be safely removed to stop drug delivery. Although this approach represents a potentially
effective strategy for the ultra-LA drug delivery for HIV treatment and prevention, long-time exposure to ARV,
especially during pregnancy, raises questions of safety. These concerns are exacerbated by the recent discovery
that DTG-based treatment for women in early stages of pregnancy may be associated with several cases of
severe neural tube defects (NTDs) in children whose mothers were being treated with DTG. It is thus vital to
systematically assess the teratogenic potential of long-term exposures to dolutegravir using relevant in vivo
models. Mice are an ideal animal model because they allow for rapid evaluation of drug effects, easy access to
embryos, and analysis of drug levels that is not possible in humans. We will use inbred mouse strains with
differential sensitivity to NTDs (BALB/cJ, C57BL/6J, and FVB/NJ) as tools for an accurate evaluation of the
relative risks of long-term DTG exposure under conditions that are most relevant to the use of DTG in humans:
(i) DTG exposure after a single injection of the long-acting DTG formulation designed to improve adherence to
drug regimen in humans; (ii) long-term exposure to DTG after daily oral administration as all current ARV
regimens are oral; (iii) exposure to DTG in preconception and during pregnancy. We will use acute exposure to
DTG at critical stages of embryonic development equivalent to human pregnancy at weeks 3, 4, 5, or 6 to gain
insight into the mechanism of potential DTG action during pregnancy. Specifically, this analysis will be able to
identify and classify a wide spectrum of potential teratogenic effects observed in human populations in
developmental stages of gastrulation and the beginning of neurulation, neural tube closure, the beginning
of limb development, and stages following neural tube closure, including palate formation. In addition,
we will evaluate the role of the folic acid, one of the most critical factors involved in NTDs. These data will be
critical in evaluating and interpreting the human birth defects data that will likely emerge over the next several
years. We will also provide a comprehensive analysis of DTG concentration in maternal plasma, placen...

## Key facts

- **NIH application ID:** 10246986
- **Project number:** 5R01HD100584-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Martina Kovarova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $777,388
- **Award type:** 5
- **Project period:** 2019-09-13 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246986

## Citation

> US National Institutes of Health, RePORTER application 10246986, In vivo Evaluation of Safety and Pharmacology of the Sustained Release Formulation of Dolutegravir in Pre-Conception and Early Stages of Pregnancy in Animal Models (5R01HD100584-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246986. Licensed CC0.

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