Physiologically-Based Pharmacokinetic (PBPK) Modeling of Asthma Drugs during Pregnancy - PROJECT SUMMARY/ABSTRACT This is an application for a K23 award for Dr. Kathleen M. Job, a clinical pharmacologist and young investigator pursuing patient-oriented clinical research into how pregnancy and chronic disease influences drug disposition and action. This K23 award will provide Dr. Job with support necessary for career development in the following areas: (1) advanced pharmacometric techniques; (2) pregnancy and maternal-fetal science; (3) clinical trial design and management in pregnant populations; and (4) leading an interdisciplinary research program. By acquiring these skills, Dr. Job will fulfill her career goal of becoming an independent investigator who advances clinical care by integrating physiology and pharmacology into approaches for designing, conducting, and interpreting clinical trials in pregnant individuals. To achieve these goals, Dr. Job has assembled a mentoring team comprising a primary mentor, Dr. Kevin Watt, an expert in PBPK modeling in special populations, and co-mentors, Dr. Torri Metz, a specialist in maternal-fetal medicine and clinical research, Dr. Christina Chambers, an expert in epidemiology of drugs during pregnancy and health outcomes, and Dr. André Dallmann, a leader in physiologically-based pharmacokinetic (PBPK) modeling in pregnant populations. Asthma is the most common chronic condition associated with pregnancy and affects up to 300,000 pregnancies every year in the United States. Asthma drugs are critical for achieving and maintaining proper control of asthma symptoms. The pharmacokinetics of these drugs can be affected by the altered physiology and lead to unacceptable drug-related toxicity or treatment failure. Progressive changes to physiology occur throughout pregnancy. In the current proposal, Dr. Kathleen Job will determine optimal dosing of two common asthma medications in pregnant individuals. In Aim 1, she will develop maternal-fetal PBPK models for these asthma medications. In Aim 2, she will evaluate model predictions with data from prospective clinical pharmacokinetic studies in pregnant individuals with asthma. In Aim 3, she will develop pharmacodynamic models for the drugs of interest in pregnant individuals with asthma with data collected as part of the prospective clinical pharmacokinetic studies in pregnant individuals. Findings will inform a Phase II/III Phase II/III safety and efficacy trial in pregnant individuals with asthma and build a platform that can be applied to dosing of any drug at any stage of pregnancy. This research will prepare Dr. Job to design and implement scientifically rigorous and ethical drug trials in pregnant populations.
