Background:
Dolutegravir (DTG) is a preferred first-line antiretroviral for the treatment of people living with human immunodeficiency virus type one (PLWHIV). Fifteen million PLWHIV world-wide are expected to be treated with DTG regimen by 2025. This includes pregnant women, who remain a significant infected population. Widespread DTG usage is linked to its high potency, barrier to resistance, and cost-effectiveness. Despite such benefits, potential risks of DTG-linked fetal neurodevelopmental toxicity remain a concern. To this end, novel formulation strategies are timely to maximize DTG’s therapeutic potentials while limiting adverse events during pregnancy. Thus, we posit that injectable long-acting (LA) nanoformulated DTG (NDTG) could provide improved safety by reducing fetal drug exposures compared to orally administered drug.
Methods:
Pregnant C3H/HeJ mice were treated with daily oral DTG at a human equivalent dosage (5 mg/kg). These were compared against pregnant mice injected with intramuscular (IM) NDTG given at 45 or 25 mg/kg at one or two doses, respectively. Treatment began at gestation day (GD) 0.5. DTG levels were measured in plasma of dams and in whole brain tissues of embryos at GD 17.5 using mass spectrometry. Magnetic resonance imaging (MRI) and non-targeted proteomic tests were performed on embryo brains at GD 17.5 to cross-validate pathobiological pathways.
Results:
Single (45 mg/kg) or two (25 mg/kg) IM injections of NDTG, or daily oral DTG administration (5 mg/kg) achieved equivalent therapeutic plasma DTG levels (4000-6500 ng/mL) in pregnant dams. However, five-fold lower DTG levels were observed in embryo brain following NDTG injections. For daily oral DTG, average concentrations of 196 ng/g were recorded compared to 34 ng/g and 45 ng/g for single or two IM injections of NDTG, respectively. MRI scanning of live dams was performed to acquire T1 maps of the embryo brain to assess oxidative stress. Significantly lower T1 values were noted in daily oral DTG-treated mice, whereas comparative T1 values were noted between control and NDTG-treated mice, indicating prevention of DTG-induced oxidative stress when delivered as NDTG. Proteomic profiling of embryo brain tissues demonstrated reductions in oxidative stress, mitochondrial impairments, and amelioration of impaired neurogenesis and synaptogenesis in NDTG-treated group.
Conclusions:
This work suggests that long-acting drug delivery can prevent DTG-linked neurodevelopmental deficits by limiting drug exposure to the embryo brain.
