Background
Dolutegravir (DTG) is a preferred antiretroviral drug (ARV) as a part of first-line regimen for treatment of people living with human immunodeficiency virus type one (HIV-1). This includes pregnant women or those of reproductive age. Recommended DTG usage, worldwide, is linked to the drug’s potency, high genetic barrier to resistance, limited drug-drug interactions, and cost-effectiveness. Despite such benefits, there are potential risks of DTG-associated fetal developmental toxicities. Thus, novel formulation strategies with translational potential are timely to maximize DTG’s therapeutic abilities while limiting adverse events recorded during pregnancy. Herein, we posit that long-acting (LA) injectable nanoformulated DTG (NDTG) can improve drug safety during pregnancy. This is expected by reducing drug exposures to placenta compared to orally administered drug.
Methods
Pregnant C3H/HeJ mice (dams) were treated with daily oral DTG at a human equivalent dosage (5 mg/kg; mouse weight) from gestation day (GD) 0.5 to GD 16.5. This oral treatment was compared against pregnant mice injected with single intramuscular (IM) NDTG given at 45 mg/kg (mouse weight) at GD 0.5. Vehicle-treated group served as controls. DTG levels were measured in plasma of dams and in placenta tissues at GD 17.5 by mass spectrometry. As matrix metalloproteinases (MMPs) influence placental vascular restructuring and placenta morphogenesis, MMPs activities were determined in placentas at GD 17.5 by fluorometric assay to compare safety.
Results
Both daily oral DTG administration and single IM injection of NDTG achieved equivalent therapeutic plasma drug levels (5300-6400 ng/mL) in pregnant dams. However, comparatively, two-fold lower DTG levels were quantified in placentas following NDTG injections. Specifically, an average of 1546 ng/g and 693 ng/g of DTG concentrations were measured in placenta tissues of mice treated with daily oral DTG and injectable NDTG, respectively. Higher drug levels paralleled significantly higher MMPs activities in placentas of daily oral DTG-treated mice compared to vehicle-treated (control) mice. Notably, comparative MMPs activities were recorded between control and NDTG-treated mice, suggesting the prevention of DTG-induced alterations in MMPs functions in placenta when delivered as LA injectable formulation.
Conclusions
The data suggest that long-acting drug delivery can prevent DTG-linked developmental deficits during pregnancy by limiting placenta-fetal drug exposures.