Effect of Obesity on Pantoprazole Pharmacokinetics and Pharmacodynamics in Children

肥胖对儿童泮托拉唑药代动力学和药效学的影响

基本信息

批准号：
10318960
负责人：
Valentina Shakhnovich
金额：
$ 18.86万
依托单位：
CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318960
关键词：
Acids Affect Anatomy Azithromycin Biological Blood flow Body Weight Body Weight decreased CYP2C19 gene CYP3A4 gene Child Childhood Chronic Cities Clinical Clinical Pharmacology Clinical Trials Computer Models Computer software Consensus Cytochrome P450 Data Discipline Disease Doctor of Pharmacy Doctor of Philosophy Dose Drug Exposure Drug Kinetics Drug Modelings Environment Enzymes Epidemic Exposure to Faculty Family Frequencies Functional disorder Funding Gastroenterologist Gastroenterology Gastroesophageal reflux disease Gastrointestinal Diseases Genetic Genotype Goals Guidelines Hepatic Hypertension Impairment Inflammation Intravenous Investigation Kansas Knowledge Lead Light Liver Mathematics Measures Mediating Medical Mentored Patient-Oriented Research Career Development Award Mentors Metabolic Biotransformation Modeling Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Outcome Overweight Pathway interactions Pediatrics Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Pharmacology Pharmacotherapy Phenotype Physicians Physiological Physiology Population Precision therapeutics Process Proton Pump Inhibitors Provider Public Health Publishing Research Research Personnel Research Training Risk Scientist Selective Serotonin Reuptake Inhibitor System Testing Therapeutic Therapeutic Index Time Training United States National Institutes of Health Update Work base biological systems career clinically relevant comorbidity curve fitting design dose individualization drug clearance drug disposition drug efficacy drug metabolism education planning enzyme activity genetic pedigree in vivo inter-individual variation knowledge base liver inflammation meetings obese patients obesity in children pediatrician peer pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics post-doctoral training predictive modeling programs prospective response simulation skills

项目摘要

PROJECT SUMMARY Pediatric obesity has reached epidemic proportions, with >30% children meeting criteria for overweight/obese. The alarming obesity epidemic brings with it increasing need for pediatricians to treat chronic obesity-related comorbidities (e.g., GERD) that frequently require long-term medical management. Yet, guidelines are lacking for optimal dosing of medications in this population. The proposed investigation builds on my recently published findings, from two independent prospective investigations that demonstrate increased systemic exposure to the proton pump inhibitor (PPI) pantoprazole in obese vs. non-obese children, suggesting slower PPI drug clearance in obesity. Using intravenous pantoprazole as a model drug probe for the hepatic drug metabolizing pathway CYP2C19, I will test the hypothesis that hepatic adiposity underlies the observed reduction in pantoprazole clearance, and that weight-reduction reverses alterations in liver adiposity, hepatic drug clearance and drug effect. Understanding of the biologic and physiologic mechanisms underlying altered drug metabolism and clearance is the first step toward developing accurate predictive models for optimizing the dose selection of PPIs, and other drugs commonly prescribed to obese patients. Postdoctoral training in an NIH-funded pediatric clinical pharmacology program at Children's Mercy Kansas City (CMKC; T32HD069038) prepared me well for a research-focused career in pediatric therapeutics by providing didactic training in curve fitting and compartmental/noncompartmental pharmacokinetic analysis; however, clinical pharmacology training has limited exposure to quantitative systems pharmacology, a biomedical discipline that uses mathematical computer models to characterize interactions of biological systems, disease processes and pharmacology, to individualize drug therapeutics in a variety of circumstances. The K23 mechanism will enable me to build on my basic pharmacology skill-set and pursue this advanced training, essential for developing physiololgically-based pharmacokinetic and pharmacodynamic (PBPK/PD) models for simulating and predicting the drug doseàconcentrationàresponse relationship for children with gastrointestinal disorders, starting with PPI dosing for obese children, who are disproportionately affected by GERD. To test the validity of the PBPK/PD models that I develop, I will need to design, conduct and effectively lead prospective longitudinal clinical trials, a mentored-research opportunity afforded to me by this K23. To expand my models to other drugs commonly prescribed to children, I will also need to update my knowledge base of drug metabolizing enzymes beyond CYP2C19, as proposed in my Education Plan. As a pediatric gastroenterologist and clinical pharmacologist at CMH, with 75% protected research time, a mentoring team comprised of expert NIH-funded faculty, lead by pharmacogenomics expert J. Steven Leeder, PharmD, PhD, I have the requisite institutional support, pedigree and academic environment to accomplish the research and training goals described in this K23 application. !

项目概要儿童肥胖已达到流行病的程度，超过 30% 的儿童符合超重/肥胖标准。令人震惊的肥胖流行病导致儿科医生治疗慢性肥胖相关疾病的需求日益增加经常需要长期医疗管理的合并症（例如胃食管反流病），但缺乏指南。拟议的调查建立在我最近的基础上。发表的研究结果来自两项独立的前瞻性调查，表明系统性增加与非肥胖儿童相比，肥胖儿童接触质子泵抑制剂 (PPI) 泮托拉唑的速度较慢使用静脉注射泮托拉唑作为肝脏药物的模型药物探针在肥胖症中的 PPI 药物清除。代谢途径 CYP2C19，我将检验以下假设：肝脏肥胖是观察到的现象的基础泮托拉唑清除率降低，体重减轻可逆转肝脏肥胖、肝病的改变了解药物清除和药物作用的生物学和生理机制。药物代谢和清除是开发准确的预测模型以优化的第一步 PPI 和其他在博士后培训中常用的药物的剂量选择。 NIH 资助的堪萨斯城儿童慈善中心的儿科临床药理学项目（CMKC；T32HD069038）通过提供曲线教学培训，为我在儿科治疗领域的研究型职业生涯做好了准备然而，拟合和区室/非区室药代动力学分析；培训对定量系统药理学的接触有限，定量系统药理学是一门生物医学学科，使用数学计算机模型来表征生物系统、疾病过程和疾病之间的相互作用 K23 机制将使药理学能够在各种情况下实现个体化药物治疗。我要以我的基本药理学技能为基础，并接受这种高级培训，这对于发展至关重要基于生理学的药代动力学和药效学 (PBPK/PD) 模型，用于模拟和预测胃肠道疾病儿童的药物剂量/浓度/反应关系，从肥胖儿童的 PPI 剂量开始，这些儿童受 GERD 的影响尤为严重，以测试其有效性。我开发的 PBPK/PD 模型，我需要设计、实施和有效领导纵向前瞻性临床试验，K23 为我提供了一个指导研究的机会，将我的模型扩展到其他领域。通常给儿童开药，我也需要更新我的药物代谢知识库 CYP2C19 以外的酶，正如我作为一名儿科胃肠病学家和临床医生所提出的。 CMH 的药理学家，拥有 75% 受保护的研究时间，由 NIH 资助的专家组成的指导团队由药物基因组学专家 J. Steven Leeder 领导的教职人员，药学博士，哲学博士，我拥有必要的机构实现本文所述研究和培训目标的支持、血统和学术环境 K23应用程序。！