Quetiapine Pharmacokinetics Across Pregnancy

Poor birth outcomes (i.e., low birth weight, preterm birth), increased risk of pregnancy complications (placental abnormalities, preeclampsia), and increased mortality are associated with untreated bipolar disorder (BD) and schizophrenia (SCHZ) in pregnancy. The use of second generation antipsychotics (SGA) indicated for the treatment of SCHZ and BD has more than doubled in pregnant women in the past decade. Yet, evidenced-based algorithms to guide dosing of SGAs are lacking. This application proposes an interdisciplinary approach to understand the pharmacokinetics of medication in pregnancy, specifically the SGA quetiapine. Dr. Clark is a perinatal psychiatrist who proposes the PhRMA Clinical Pharmacology Foundation Award investigation entitled, “Pharmacokinetics of Quetiapine Across Pregnancy.” Dr. Clark’s expert interdisciplinary mentorship team includes Lead Mentor, Katherine L. Wisner, MD, MS (psychiatry); Catherine Stika, MD (obstetrics); Michael Avram, PhD (pharmacokinetics); and Alfred George, MD (pharmacogenomics). With the guidance of her mentorship team, research experiences in pharmacology, and perinatal mental health insights, Dr. Clark will investigate the degree to which changes in quetiapine pharmacokinetics, especially quetiapine elimination clearance, across pregnancy impacts efficacy, toxicity, maternal-to-umbilical cord plasma concentration ratios, and maternal-to-cerebrospinal fluid plasma concentration ratios. To achieve this goal, Dr. Clark will: 1) implement a longitudinal pharmacokinetic protocol to characterize the elimination clearance of quetiapine and its major active metabolite across pregnancy and postpartum; 2) assess mood symptoms, side effects, and function to determine association between plasma drug concentrations and efficacy and toxicity; and 3) obtain maternal and umbilical cord samples at delivery to examine fetal exposure to quetiapine in pregnancy through maternal-to-cord plasma concentrations ratios of quetiapine and its major active metabolite. The effect of the genomic variants ABCB1 *6, *7, and *8 on quetiapine plasma concentrations and maternal-to-cord and maternal-to-CSF concentration ratios will be investigated. Furthermore, through this project, Dr. Clark will: (1) broaden her proficiency and expertise in the design of pharmacokinetic protocols that examine metabolic pathways across pregnancy, labor and delivery, and postpartum; (2) develop a solid understanding of advanced topics in clinical pharmacology, including laboratory procedures involved in drug concentration measurement by LC-MS/MS, pharmacokinetic modelling and simulation, and statistical analysis and interpretation of pharmacokinetic data; (3) gain knowledge and experience in pharmacogenomics, including assessing and understanding genetic variation, analyzing genotype and phenotype relationships, research methods, study design, analytical methods, and variable drug response; and (4) improve grant and manuscript writing skills. The long term goal of this project is to develop personalized psychotropic medication dosing algorithms informed by longitudinal pharmacokinetic data and pharmacogenomics to improve the pregnancy outcomes of women with serious mental illness.