Project Summary Pregnant women are generally excluded from drug development trials due to safety concerns and as a result pregnant women living with HIV (PWLH) frequently receive newly licensed antiretrovirals (ARVs) in the absence of pregnancy-specific safety and pharmacokinetic (PK) data. Moreover, PK data from non-pregnant adults cannot be extrapolated to inform dosing during pregnancy due to physiologic and anatomic changes associated with pregnancy that affect drug disposition. The NIH-supported International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1026s study (NCT000422890) was designed to fill this knowledge gap by performing PK and safety studies in PWLH receiving ARVs. To date, P1026s has enrolled over 1,000 pregnant women from the USA and internationally and the data generated have supported ARV treatment guidelines and product label changes, including the recent FDA recommendation against use of cobicistat-boosted regimens in PWLH. The ongoing development of long-acting (LA) extended release ARV formulations administered monthly, or less frequently, is one of the most exciting innovations in HIV therapeutics since the introduction of antiretroviral therapy (ART) in the mid-1990s. The first LA ARVs to be licensed are likely to be intramuscular formulations of the integrase strand transfer inhibitor (INSTI) cabotegravir (CAB) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV). CAB shares its metabolic pathway with the preferred 1st-line INSTI dolutegravir (DTG). Pregnant women have been excluded from the phase III clinical trials of LA-CAB/RPV. Evaluation of LA formulations in PWLH poses special considerations including risks to mothers and their fetuses. The application of robust physiologically based pharmacokinetic (PBPK) models developed with P1026s data will help predict maternal/fetal drug disposition of new oral and LA-ARVs during and after pregnancy, which in turn, will accelerate their study in pregnant women. We are currently collaborating with the U.S. FDA to develop PBPK models for ARVs during pregnancy (FDA Critical Path Initiative Grant #F17-58) but our experience in this area has confirmed that pregnancy PBPK models are currently limited by a lack of system specific data describing pregnancy related changes in protein binding and metabolic pathways. Our objective in this application is to quantify (1) unbound concentrations and (2) primary metabolite-to-parent ratios of DTG and RPV, as well as the INSTI raltegravir (RAL) during the 2nd and 3rd trimesters of pregnancy and postpartum to strengthen the framework of our PBPK models to predict drug disposition in pregnancy. We will leverage stored biorepository samples collected within P1026s from participants in several completed arms to describe pregnancy related changes in protein binding and metabolic pathways. This work is innovative as it confronts the challenge of quantifying therapeutically active drug concentrations and metabolites in the context of pregnancy-induced changes. This information can then be included in our PBPK models to improve the prediction of maternal/fetal exposures and guide dosing of novel oral and LA-ARVs in this special population.

Narrative Pregnant women are routinely left out of drug development programs and the NIH-supported International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1026s study was designed to fill this knowledge gap by performing pharmacokinetic (PK) and safety studies in pregnant women living with HIV. The development of long-acting (LA) formulations of antiretrovirals (ARVs) is an exciting innovation in HIV prevention and treatment but as with previous ARVs pregnant women have been excluded from studies during their development. We will use stored plasma samples from pregnant women enrolled in P1026s to measure unbound therapeutically active drug concentrations and metabolites of antiretrovirals that will strengthen physiologically-based pharmacokinetic (PBPK) models we are developing with the US FDA in order to predict maternal/fetal drug disposition of new oral and LA-ARVs during and after pregnancy, which in turn, will accelerate their study in pregnant women.