Antiretroviral treatment of HIV infection in pregnant women is necessary for the prevention of mother-to-child transmission (PMCT). However, due to physiological changes occurring during pregnancy the pharmacokinetics of antiretroviral drugs can be drastically altered, resulting in lower maternal plasma concentrations. This can lead to the development of resistance, treatment failure and transmission of (resistant) virus to the newborn. Currently, none of the antiretroviral drugs is registered for treatment in pregnancy and evidence-based dose adjustments are not available. A better understanding of the mechanisms underlying the absorption, distribution, metabolism and excretion (ADME) of antiretroviral drugs in healthy volunteers and the mechanistic changes that occur in these processes in non-pregnant as well as pregnant HIV+ women can aid in designing rational dosing adjustments. Specific interest in pregnancy also relates to placental disposition and passage through the blood-placenta barrier of antiretroviral agents (fetal exposure). E.g. it is unclear whether placental accumulation/transfer adds to effective PMTCT and/or increases the risk of toxicity in utero. In this project, we aim to improve the assessment of safety/benefit ratios and facilitate the development of rational dosing regimens of antiretroviral drugs during pregnancy. Preclinical and clinical studies will be combined in taking a unique physiologically-based pharmacokinetic modeling approach
