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

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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, placenta, amniotic fluid and embryonic tissues during chronic daily oral DTG administration, after a single dose of a long- acting formulation of DTG and after an acute oral dose of DTG at critical stages of embryonic development. This will allow us to correlate concentration of DTG in embryonic tissues with observed birth defects. Evaluation of teratogenic effect of long-term oral administration of DTG and a long-acting DTG formulation using mouse strains with differential sensitivities to NTD represents a novel and valuable approach to demonstrate the safety profile of DTG in pre-conception and during early stages of pregnancy.