Medications in Pregnancy: Defining Exposure

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DESCRIPTION (provided by applicant): This is an application for RFA-OD-02-002 to fund a Specialized Center of Research on Sex and Gender Factors Affecting Women's Health representing the collaborative efforts of five departments and two academic institutions. The central theme of the application is "pharmacokinetic, pharmacodynamic, and pharmacogenetic (PK/PD/PG) modeling of anti-epileptic drugs (AED) and psychotropic medications during pregnancy and lactation using both human and rodent paradigms: defining fetal/neonatal exposure and influence on obstetrical outcome" ' The primary objectives of the center include: 1) PK/PD/PG modeling of anti-epileptic drugs (AED) and psychotropic medications antidepressants, lithium) during pregnancy and lactation. These novel data will provide information about the metabolism, distribution, and extent of fetal/neonatal exposure to these medications. The data for this modeling will be obtained from women with neurological disorders (Epilepsy, Tourette's Syndrome) and mental illness (Bipolar Disorder, Major Depression, Obsessive Compulsive Disorder, Panic Disorder). These patient populations were selected based on the typical chronic course of illness and utilization of similar medications between the groups. The PK/PD modeling from subjects with different illnesses and ethnic groups enhances the pharmacogenetic (PG) comparison of metabolic capacity and protein binding. 2) These clinical data will be complemented by a series of laboratory animal studies in two strains of rodent (one deficient in 2D6 activity) to provide fetal and neonatal central nervous system (CNS) tissue concentrations, neonatal CNS clearance, and neurotransmitter receptor effects of antenatal and postnatal exposure to AEDs and psychotropic medications. 3) Prospective assessment of these women will provide documentation of all additional exposures (prescription medications, over the counter preparations, herbal remedies, maternal illness events, environmental toxins) and delineation of the course of illness during pregnancy and postpartum. The ultimate clinical import of these data will be clarification of the factors influencing medication metabolism and distribution, thereby providing an estimate fetal/neonatal exposure, factors influencing such exposure, and novel data regarding the potential "dose versus outcome" comparison. The multidisciplinary team of this center application represent two academic medical centers and five departments organized into 2 clinical projects, 1 laboratory investigation, supported by 3 core components and an executive committee with extensive research/clinical experience. The achievement of the objectives address several research priority areas noted in ORWH Agenda for Research on Women's Health for the 21st century.