Pharmacokinetics of Risperidone Across Pregnancy

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PROJECT ABSTRACT 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). 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 women with serious mental illness. To achieve this goal, Dr. Clark will: 1) as a training aim – will classify pregnancy subjects taking selective serotonin reuptake inhibitors (SSRI) by CYPD6 and ABCB1 genotype to determine their effect on metabolism, SSRI transport, and depressive symptoms and toxicity; 2) implement a longitudinal PK protocol to characterize the elimination clearance of RISP across pregnancy and postpartum; determine CYP2D6 genotypes and the relationship between enzymatic activity and clinical outcomes; 3) assess PK changes on mood symptoms, side effects, function 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. The impact of genetic variants of the transporter gene, ABCB1, on RISP maternal plasma-to-cerebrospinal fluid ratios and RISP maternal-to-cord plasma concentrations ratios will be determined. 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; (3) Develop a solid understanding of advanced topics in clinical pharmacology; and (4) Improve grant and manuscript writing skills.