LOC-IMPAACT Leadership GroupPharmacokinetics and Safety of Remdesivir for Treatment of COVID-19 in Pregnant Women in the US

PROJECT SUMMARY Remdesivir, the first drug with preliminary evidence of efficacy for treatment of COVID-19, has recently been awarded Emergency Use Authorization from the FDA for use in hospitalized patients with documented COVID- 19. There are no documented pharmacokinetic (PK) and limited safety data available regarding use in pregnancy. The physiological changes associated with pregnancy can have a dramatic impact on drug disposition, and use of therapeutic agents during pregnancy poses unique safety concerns. The aims of the proposed Phase IV prospective, open label, non-randomized study are to evaluate the PK (Specific Aim 1) and safety (Specific Aim 2) of remdesivir provided through a compassionate use program or open access protocol in 20 hospitalized pregnant women for treatment of symptoms related to COVID-19, using a well-established study approach and leveraging the extensive infrastructure of the NIH-sponsored International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network and in collaboration with Gilead Sciences. The study will be conducted at multiple experienced IMPAACT-affiliated sites in the US with proven access to the study population. Hospitalized pregnant women >18 years of age with COVID-19 scheduled to receive remdesivir as part of clinical care will be eligible for enrollment if willing and able to provide informed consent or if a legally recognized representative can do so on her behalf. The primary outcome measure will be a comparison of remdesivir PK parameters from study participants (pregnant women) with those in non-pregnant adults. The primary PK endpoints are remdesivir and its major metabolite, GS-441524, AUC0-24h at Day 1, and GS-441524 AUCtau after last dose. Intensive and sparse sampling remdesivir concentrations will be used in a population PK analysis to assess the impact of covariates such as stage of pregnancy and severity of COVID- 19 disease on remdesivir PK parameters. Plasma remdesivir and GS-441524 concentrations will be quantified in the laboratory being used for ongoing Gilead-supported studies of remdesivir in non-pregnant adults, ensuring comparability. At entry and after the last dose, safety monitoring will include liver and renal function tests and complete blood count (if not obtained within 24 hours for clinical care) and medical record abstraction for other laboratory test results and clinical events. Medical record abstraction for laboratory test results and clinical events will also be performed at 4 weeks postdosing and after labor and delivery. The proposed study will provide urgently needed pregnancy-specific clinical pharmacology data that will ensure that remdesivir can be used safely and effectively in pregnant women as rapidly as possible. This research could also serve as a model to rapidly provide pregnancy PK and safety data for other COVID- therapeutics as they become available.