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：
10084292
负责人：
Valentina Shakhnovich
金额：
$ 18.85万
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/10084292
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 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. !

项目摘要小儿肥胖已经达到了流行比例，> 30％的儿童符合超重/肥胖的标准。令人震惊的肥胖流行使儿科医生越来越需要治疗慢性肥胖有关经常需要长期医疗管理的合并症（例如GERD）。但是，指南缺乏最佳剂量在该人群中。拟议的调查是基于我最近的发表的发现，来自两项独立的前瞻性调查，这些调查表明系统性增加暴露于肥胖儿童中的质子泵抑制剂（PPI）pantraprazole，表明较慢肥胖症中的PPI药物清除率。使用静脉注射吡唑唑作为肝药物的模型药物探针代谢途径CYP2C19，我将检验以下假设：肝肥胖是观察到的减少pantraprozole清除率，减少体重逆转肝肥胖的改变，肝药物清除和药物效应。了解改变的生物学和生理机制改变了药物代谢和清除是开发优化准确预测模型的第一步 PPI的剂量选择以及其他通常针对肥胖患者处方的药物。博士后培训 NIH资助的小儿临床药理学计划在堪萨斯城儿童慈悲（CMKC; T32HD069038）通过在曲线中提供教学训练，我为以研究为重点的儿科疗法做好了很好的准备安装和隔室/非各个分节药代动力学分析；但是，临床药理学培训对定量系统药理学的接触有限，这是一种使用的生物医学学科数学计算机模型以表征生物系统，疾病过程和药理学，以在各种情况下个性化药物治疗。 K23机制将启用我要基于我的基本药理学技能，并接受这项高级培训，对于开发基于物理的药代动力学和药效学（PBPK/PD）模型，用于模拟和预测患有胃肠道疾病儿童的药物剂量àResponseàResponse关系，从肥胖儿童的PPI给药，他们受GERD的影响不成比例。测试有效性我开发的PBPK/PD模型，我需要设计，进行并有效地领导前瞻性纵向临床试验是这个K23为我提供的心理研究机会。将我的模型扩展到其他通常向儿童开处方的药物，我还需要更新我的毒品代谢知识库正如我的教育计划中提出的那样，CYP2C19以外的酶。作为儿科胃肠病学家和临床 CMH的药物学家，有75％的受保护时间的研究时间，一支心理团队完成了NIH资助的专家由药物基因组学专家J.史蒂文·利德（J. Steven Leeder）领导的教师支持，谱系和学术环境，以实现此处描述的研究和培训目标 K23申请。呢