Pharmacokinetics of Risperidone Across Pregnancy

利培酮在妊娠期的药代动力学

• 批准号: 9243703
• 负责人: Crystal T Clark
• 金额: $ 16.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243703
• 关键词: ABCB1 gene; Adverse effects; Affect; Algorithms; Alleles; Antipsychotic Agents; Bipolar Disorder; Birth; Blood - brain barrier anatomy; CYP2D6 gene; Cerebrospinal Fluid; Child; Clinical; Clinical Pharmacology; Cytochrome P450; Cytochromes; DNA; Data; Data Analyses; Development; Discipline of obstetrics; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Efflux; Drug Kinetics; Emotional; Funding; Future; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Health Personnel; Individual; Intestines; Investigation; Investigational Drugs; Knowledge; Low Birth Weight Infant; Manuscripts; Medication Management; Mental Health; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolism; Mothers; National Institute of Child Health and Human Development; Obstetric Fetal Pharmacology; Optimizing Pharmacotherapy for Depression during Pregnancy; Outcome; Participant; Perinatal; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacological Treatment; Phenotype; Physiological; Placenta; Plasma; Play; Postpartum Period; Postpartum Women; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Protocols documentation; Psychiatrist; Psychiatry; Psychotropic Drugs; Recurrence; Research; Research Design; Resources; Risk; Risperidone; Role; Sampling; Schizophrenia; Selective Serotonin Reuptake Inhibitor; Solid; Structure; Symptoms; Techniques; Time; Toxic effect; Training; Umbilical Cord Blood; Umbilical cord structure; Variant; Venous; Woman; Writing; child bearing; depressive symptoms; drug efficacy; early onset; evidence base; experience; fetal; genetic variant; improved; mood symptom; mortality; predict clinical outcome; prenatal exposure; reproductive; response; severe mental illness; skills; transport inhibitor; treatment response

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.

项目摘要 出生结果不佳（即低出生体重，早产），妊娠并发症的风险增加 （胎盘异常，子痫前期）和死亡率增加与未处理的躁郁症有关 （BD）和精神分裂症（SCHZ）怀孕。使用第二代抗精神病药（SGA）表示 在过去的十年中，孕妇的Schz和BD的治疗增加了一倍以上。然而， 缺乏基于证据的算法来指导SGA的给药。此申请对优先级的响应 产科胎儿药理学研究中心，并寻求建立跨学科培训 研究药物基因组学（PGX）对药代动力学（PK）和药效学的影响 SGA的（PD）怀孕，特别是利培酮（RISP）。 克拉克博士是一位围产期精神病医生，他建议对受过指导患者的重新提出申请 - 面向研究职业发展奖（K23）项目，标题为“利培酮的药代动力学 克拉克博士的专家跨学科心态团队包括主要导师凯瑟琳·L。 M.D. Wisner，M.S。 （精神病学）；联合促进导师Alfred George，医学博士（PGX）；还有迈克尔的委员 Avram博士（PK）和凯瑟琳·斯蒂卡（Catherine Stika），医学博士（妇产科）。 这项研究的长期目标是建立精神药物给药算法。 PK，PD和PGX数据可改善精神严重的女性的心理健康和怀孕成果 疾病。为了实现这一目标，克拉克博士将：1）作为培训目标 - 将对怀孕对象进行分类 CYPD6和ABCB1基因型的选择性5-羟色胺再摄取抑制剂（SSRI），以确定它们对它们对它们的影响 代谢，SSRI运输以及抑郁症状和毒性； 2）实施纵向PK协议 表征在妊娠和产后消除RISP的消除；确定CYP2D6 基因型以及酶活性与临床结局之间的关系； 3）评估PK变化 情绪症状，副作用，怀孕期间和产后功能； 4）获取材料，脐带 绳索（动脉和静脉）样品，以检查RISP的等离子与频线浓度比。这 转运蛋白基因ABCB1的遗传变异对RISP MATER血浆到脑脊液的影响 将确定比率和RISP Matal-cord血浆浓度比。克拉克博士寻求其他 培训：（1）开发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）对遗传变异有透彻的了解 以及与个体间和内部的经验评估基因型和表型关系 PK和PD的变异性； （3）对临床药理学的先进主题有牢固的了解；和 （4）提高赠款和手稿写作技巧。