Pharmacokinetics of Risperidone 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 responds to the priorities of the Obstetric Fetal Pharmacology Research Center and seeks to establish interdisciplinary training to investigate the impact of pharmacogenomics (PGx) on the pharmacokinetics (PK) and pharmacodynamics (PD) of SGAs in pregnancy, specifically risperidone (RISP). Dr. Clark is a Perinatal Psychiatrist who proposes the resubmission application for the Mentored Patient-Oriented Research Career Development Award (K23) project entitled, “Pharmacokinetics of Risperidone Across Pregnancy.” Dr. Clark’s expert interdisciplinary mentorship team includes Primary Mentor, Katherine L. Wisner, M.D., M.S. (psychiatry); Co-Primary Mentor Alfred George, M.D. (PGx); and Co-Mentors Michael Avram, Ph.D. (PK) and Catherine Stika, M.D. (obstetrics). Dr. Clark will gain valuable hands-on training in PGx through the unique and novel infrastructure offered by the NICHD-funded Optimizing Pharmacotherapy for Depression During Pregnancy (OPTI-MOM) U54 center grant (1U54HD085601) awarded to her mentorship team. Dr. Clark will explore the impact of genetic variants on PKs and clinical outcomes of SSRIs. With this training she will pursue a separate pilot study of RISP PK that explores the impact of genetic variants on RISP plasma concentration. The long-term goal of this research is to establish psychotropic medication dosing algorithms informed by PK, PD, and PGx data to improve mental health and pregnancy outcomes for pregnant women with serious mental illness. To achieve this goal, Dr. Clark will: 1) as a training aim - classify subjects taking selective serotonin reuptake inhibitors (SSRIs) by CYPD6 and ABCB1 genotype to determine their effect on metabolism and SSRI transport and on the recurrence of depressive symptoms and toxicity across pregnancy and postpartum; 2) implement a longitudinal PK protocol to characterize the elimination clearance of RISP and its active metabolite, 9-OH, across pregnancy and postpartum; participant CYP2D6 genotypes will be characterized to determine the relationship between enzymatic activity and clinical outcomes; 3) assess mood symptoms, side effects, and function to determine the effect of PK changes on symptoms and toxicity during pregnancy and postpartum; and 4) obtain maternal, umbilical cord (arterial and venous) samples to examine the plasma-to-umbilical cord concentrations ratios of RISP and its active metabolite, 9-OH. Dr. Clark will also obtain cerebrospinal fluid (CSF) samples and umbilical cord blood to explore the impact of genetic variants of the transporter gene, ABCB1, on RISP maternal plasma-to-CSF ratios and RISP maternal-to-cord plasma concentrations ratios. Dr. Clark seeks additional training to: (1) To develop expertise in study design and data analysis that includes consideration of PGx contributions of interindividual PK and PD variability; (2) Gain a thorough understanding of genetic variation and experience assessing genotypic and phenotypic relationships to interindividual and intraindividual variability in PKs and PDs, and as a result, drug efficacy and toxicity. (3) Devel