Effect of Obesity on Pantoprazole Pharmacokinetics and Pharmacodynamics in Children

项目摘要 儿童肥胖已达到流行病的比例，超过30%的儿童符合超重/肥胖的标准。 令人担忧的肥胖流行病带来了越来越多的需要儿科医生治疗慢性肥胖相关的 合并症（例如，GERD），经常需要长期的医疗管理。然而，缺乏指导方针， 在这一人群中进行最佳药物剂量的研究。拟议中的调查建立在我最近 两项独立的前瞻性调查结果表明， 在肥胖儿童与非肥胖儿童中暴露于质子泵抑制剂（PPI）泮托拉唑， 肥胖患者的PPI药物清除率。静脉注射泮托拉唑作为肝脏药物的模型药物探针 代谢途径CYP2C19，我将测试假设，肝肥胖的基础上观察到的 泮托拉唑清除率降低，体重减轻逆转了肝脏肥胖，肝脏 药物清除率和药物作用。理解改变的生物和生理机制 药物代谢和清除是开发精确预测模型的第一步， PPI的剂量选择，以及其他肥胖患者常用的药物。博士后培训 儿童慈善堪萨斯城NIH资助的儿科临床药理学项目（CMKC; T32HD 069038） 通过提供曲线教学培训，我为我在儿科治疗学领域的研究工作做好了准备。 拟合和房室/非房室药代动力学分析;然而，临床药理学 培训限制了对定量系统药理学的接触，这是一门生物医学学科， 数学计算机模型，以表征生物系统，疾病过程和 药理学，在各种情况下个性化药物治疗。K23机制将使 我建立在我的基本药理学技能，并追求这种先进的培训，发展必不可少的 基于生理学的药代动力学和药效学（PBPK/PD）模型， 预测胃肠道疾病患儿的药物剂量-浓度-反应关系， 从肥胖儿童的PPI剂量开始，他们不成比例地受到GERD的影响。检验…的有效性 我开发的PBPK/PD模型，我将需要设计，执行和有效地领导前瞻性纵向 临床试验，这是K23给我的一个指导研究的机会。将我的模型扩展到其他 我也需要更新我的药物代谢知识库 CYP2C19酶，正如我的教育计划中所建议的那样。作为一名儿科胃肠病学家和临床 CMH的药理学家，75%的研究时间受到保护，一个由NIH资助的专家组成的指导团队 教师，由药物基因组学专家J.史蒂文利德，药学博士，博士领导，我有必要的机构 支持，血统和学术环境，以实现本文件中描述的研究和培训目标 K23应用 !

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. !