ABSTRACT
Antiviral therapy (AVT) has been a pharmaceutical success story for the treatment of both acute and
chronic viral infections in pregnant people, their developing fetuses, and newborns. Despite this, serious
adverse effects can occur due to antiviral drug-hormone interactions (DHIs). These adverse effects can result
in a substantial risk to both the patient, her fetus, and the newborn. Disruption of steroid hormone homeostasis
is critical in this phenomenon, with reports associating AVT with dysregulation of estradiol levels in pregnancy,
low birth weight and transient adrenal insufficiency in neonates, and neurodevelopmental impairments in
children later in life. These serious adverse effects require our attention in order to understand the toxicological
processes involved and inherent risks for some of the most vulnerable population groups, which is a primary
goal of this NIH funding announcement, (PAR-23-130). In order to reduce the risk for adverse health outcomes
with these drugs, we must first understand the underlying cause(s) for the toxicities associated with them. The
hepatic drug and steroid metabolizing enzymes, e.g. the cytochrome P450 (CYP) and UDP
glucuronosyltransferase (UGT) enzymes, are equally important in drug disposition and steroid homeostasis,
thus they sit at the interface of the DHIs attributable to AVT. Our central hypothesis is that antiviral therapy
interferes with the endogenous processes important for steroid hormone biosynthesis and metabolism via
enzyme inhibition, induction, and/or activation and that hepatic enzymes, in particular CYP and UGT enzymes,
are central in this interplay. Our approach consists of: 1) determining the effects of antiviral medications on
estradiol homeostasis during pregnancy in order to generate physiologically-based pharmacokinetic (PBPK)
models for DHI prediction of risk for estradiol metabolic imbalance, 2) quantifying the extent of antiviral drug-
hormone interaction for the human steroidogenic CYP3A7-dependent fetoplacental endocrine signaling
pathway, and 3) assessing the effect of lopinavir-ritonavir on hepatic bile acid homeostasis driven by CYP3A
ontogeny in early infancy to understand the potential risk for long-term bile acid dysregulation. We expect that
the successful completion of these specific aims will provide us with advanced mechanistic models to explain
antiviral DHIs and will allow us to predict and prevent future antiviral-based adverse DHIs in some of the most
vulnerable and understudied patient groups. This, in turn, will limit life-threatening complications and improve
health outcomes for women and children treated with life-saving antiviral medications, an important goal of the
NIH and this funding announcement (PAR-23-130).
