Model-Informed Evaluation of Hydroxyurea Exposure in Special Populations

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PROJECT SUMMARY/ABSTRACT This K01 application describes a 5-year training plan designed to support Dr. Dong to gain additional skill and knowledge to transition to a special research niche of understanding pharmacotherapy during pregnancy and lactation. Dr. Dong is an Assistant Professor in the Division of Clinical Pharmacology at Cincinnati Children’s Hospital Medical Center (CCHMC). The designed study will leverage her research expertise in pharmacokinetic (PK) modeling coupled with a world renowned research center on sickle cell anemia (SCA) and hydroxyurea pharmacotherapy at CCHMC. SCA is one of the most common genetic disorders affecting millions worldwide. Improvements in medical care have transitioned SCA from a disease of childhood into a long-term chronic illness, and reproductive health has emerged as a significant component in SCA care. Hydroxyurea is an effective and safe pharmacotherapy to ameliorate the clinical course of SCA. However, concerns of toxic effects on fetuses and neonates have limited the use of hydroxyurea in pregnant or lactating women. Without providing continuous management, patients with SCA may develop severe complications such as pain crisis and stroke during pregnancy and postpartum period. So far, no clinical trials could be conducted in these vulnerable populations due to ethical constraints, and significant knowledge gaps remain in our understanding of hydroxyurea placental transfer in humans and its exposure in the fetus and breastfed babies. In recent years, in silico physiologically- based pharmacokinetic (PBPK) modeling has emerged as a powerful tool to predict the drug disposition during pregnancy and postpartum. The overall goal of this proposal is to evaluate hydroxyurea exposure in both mother and fetus/infant during pregnancy and lactation using whole body PBPK modeling. This proposal represents a step forward of using an innovative approach to address health disparities by improving maternal and infant health outcomes in minority populations. The study includes the following Specific Aims: 1) To quantify hydroxyurea exposure in pregnant women and the embryo/fetus using integrated PBPK models; 2) To assess hydroxyurea exposure in breastfeeding newborns and infants with integrated PBPK models; 3) To develop a clinical decision support tool in the prediction of hydroxyurea exposure in individual patients. The training goal of this K01 award is to foster Dr. Dong’s career growth to become a successful, independent, NIH funded scientist who has the expertise in whole body maternal/fetal/lactation/neonatal drug evaluation using an in silico PBPK approach and in decision support tool development. Dr. Dong will receive training from an outstanding mentorship team led by her primary mentor Dr. Vinks, an expert in quantitative clinical pharmacology, and co- mentor Dr. Ware, a highly accomplished hematologist who has led many international research efforts in hydroxyurea treatment and SCA care improvement. This mentoring team in concert with a balanced training program and excellent research project will provide a solid foundation to Dr. Dong’s career development in the field of hydroxyurea research and PBPK modeling for special populations.