Background: Effective HIV treatment during pregnancy is critically important, both for the health of women living with HIV (WLHIV) and for prevention of perinatal HIV transmission. There are knowledge gaps though, that limit our ability to deploy new effective antiretroviral therapy agents in this special population. The proposed mentored K23 application is an investigation led by Dr. Ahizechukwu Eke on the effects of pregnancy on the pharmacology of new HIV drugs, including effects on adherence measures, and on these drugs? safety in pregnant women. Candidate: Dr. Ahizechukwu Eke is a Maternal Fetal Medicine and Clinical Pharmacology-trained Physician-Scientist who has spent the past 4 years conducting research on the clinical pharmacology of drugs in pregnant women. He helped establish a cohort of pregnant women living with HIV (WLHIV) at Johns Hopkins, developed strong scientific collaborations with pharmacometricians and scientists through the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, and authored 65 PubMed-cited publications related to his research. Research:
In Aim 1, among pregnant WLHIV taking tenofovir alafenamide (TAF), Dr Eke will characterize the pharmacokinetics (PK) of tenofovir (TFV) and its active form (intracellular tenofovir diphosphate ? TFV-DP), and establish PK adherence benchmarks in pregnancy using PK modeling.
Aim 2 examines pregnancy-specific safety of TAF by exploring its association with development of metabolic syndrome in pregnant WLHIV, and Aim 3 uses physiologically based PK (PBPK) modeling to predict maternal and fetal bictegravir and doravirine concentrations, confirming results in pregnant WLHIV enrolling in a prospective multi-center PK cohort study (IMPAACT 2026). Career Development Plan: Dr. Eke?s long term goal is to become an independent physician-scientist focused on HIV therapeutics in pregnant women. His short term goals and the focus of this K23 application, are to fill the gaps in his research skillset that he and his mentoring team have identified by focusing on these objectives:1) To grow his skills in advanced PK modeling, including models that incorporate adherence, and pharmacometrics; 2) to gain skills in safety assessments in pregnancy via data analysis and focused coursework on longitudinal data analysis and pharmaco-epidemiology study design, and; 3) to understand how PBPK models are developed and can be used to facilitate drug and dose selection for pregnant women. Dr Eke plans to achieve these objectives by working with mentors with expertise directly relevant to his career goals: Dr Craig Hendrix and Kelly Dooley (Clinical Pharmacology and HIV); Dr Jeanne Sheffield (Perinatal Epidemiology, Maternal Fetal Medicine, and HIV); and Dr Joga Gobburu (Pharmacometrics, PBPK modeling). Environment: The institutional environments at both Johns Hopkins (Hendrix, Dooley and Sheffield) and the Pharmacometrics Division at the University of Maryland (Gobburu) are ideal for training and research in the pharmacology of drugs in pregnancy. The long-standing collaboration between these institutions and the strong collaboration with members of IMPAACT will provide Dr. Eke with strong mentorship to advance his research career.
Effective antiretroviral therapy is critical during pregnancy for women living with HIV (WLHIV) for the health of both the mother and the fetus, but there are knowledge gaps in pharmacology of new HIV drugs, ways to assess adherence, and safety in pregnancy that prevent efficient and effective deployment of our most promising new HIV drugs in pregnant women. The objective of this proposal is to advance our knowledge of the pharmacology and safety of several new HIV drugs -- tenofovir alafenamide (TAF), bictegravir, and doravirine--in pregnant and post-partum women, using innovative tools, such as pharmacometrics and physiologically based pharmacokinetic (PBPK) modeling. Research goals include describing TAF pharmacokinetics (PK) and adherence benchmarks in pregnancy, characterizing the risk and implications of TAF-associated metabolic syndrome in pregnant WLHIV, and predicting bictegravir and doravirine PK in pregnant women and their fetuses, with the overall goal of optimizing HIV therapeutics for pregnant WLHIV.