Pharmacokinetics of Risperidone Across Pregnancy

项目摘要 不良的生育结果（即，低出生体重、早产）、妊娠并发症风险增加 （胎盘异常，先兆子痫）和死亡率增加与未经治疗的双相情感障碍有关 (BD)妊娠期精神分裂症（Schizophrenia，SCHZ）。使用第二代抗精神病药（SGA）表明 在过去的十年中，用于治疗SCHZ和BD的药物在孕妇中增加了一倍多。然而， 缺乏基于证据的算法来指导SGA的剂量。此应用程序响应以下优先级 产科胎儿药理学研究中心，并寻求建立跨学科的培训， 研究药物基因组学（PGx）对药代动力学（PK）和药效学的影响 (PD)怀孕期间的SGAs，特别是利培酮（RISP）。 克拉克博士是一位围产期精神病学家，他为指导病人提出了重新提交申请- 定向研究职业发展奖（K23）项目，题为“利培酮的药代动力学 怀孕期间。”克拉克博士的专家跨学科导师团队包括小学导师，凯瑟琳L。 维斯纳，医学博士，M.S.（精神病学）;共同主要导师阿尔弗雷德乔治，医学博士。(PGx);和共同导师迈克尔 Avram博士(PK)和凯瑟琳·斯蒂卡医学博士（产科）。 这项研究的长期目标是建立精神药物给药算法， PK、PD和PGx数据可改善严重精神疾病女性的精神健康和妊娠结局 病为了实现这一目标，克拉克博士将：1）作为培训目标-将怀孕受试者分类， CYPD 6和ABCB 1基因型的选择性5-羟色胺再摄取抑制剂（SSRI），以确定其对 代谢，SSRI转运，抑郁症状和毒性; 2）实施纵向PK方案， 描述RISP在妊娠期和产后的消除清除率;测定CYP 2D 6 基因型和酶活性与临床结果之间的关系; 3）评估 情绪症状，副作用，功能在怀孕期间和产后;和4）获得产妇，脐 脐带（动脉和静脉）样本，以检查RISP的血浆与脐带浓度比。的 转运蛋白基因ABCB 1的遗传变异对RISP母体血浆-脑脊液的影响 将测定RISP母体与脐带血浆浓度比。克拉克博士寻求更多 培训：（1）培养研究设计和数据分析方面的专业知识，包括考虑PGx 个体间PK和PD变异性的贡献;（2）全面了解遗传变异 和经验评估基因型和表型的关系，以个体间和个体内 PK和PD的变异性;（3）对临床药理学的高级主题有深入的了解;以及 (4)提高赠款和手稿的写作技巧。

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.