Effect of Obesity on Pantoprazole Pharmacokinetics and Pharmacodynamics in Children

项目总结 儿童肥胖已经达到了流行的程度，30%的儿童符合超重/肥胖的标准。 令人担忧的肥胖症流行带来了对儿科医生治疗慢性肥胖症相关疾病的日益增长的需求 经常需要长期医疗管理的并存疾病(如GERD)。然而，缺乏指导方针。 以便在这一人群中获得最佳剂量的药物。拟议的调查是基于我最近的 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 肥胖儿童与非肥胖儿童暴露于质子泵抑制剂(PPI)潘托拉唑的研究表明，肥胖儿童的肥胖率较低 肥胖症患者PPI药物清除情况。潘托拉唑静脉注射作为肝药模型药物探针的研究 代谢途径，我将检验肝脏肥胖症是观察到的 潘托拉唑清除量的减少，体重减轻逆转了肝脏肥胖症、肝脏 药物清除和药物效应。对改变的生物和生理机制的理解 药物代谢和清除是开发准确的预测模型进行优化的第一步 PPI的剂量选择，以及肥胖症患者常用的其他药物。中国的博士后培训 美国国立卫生研究院资助的堪萨斯城儿童慈悲医院儿科临床药理学项目(CMKC；T32HD069038) 通过提供曲线教学培训，为我在儿科治疗学的研究职业生涯做好了准备 符合和间隔/非间隔药代动力学分析；然而，临床药理学 培训对定量系统药理学的接触有限，这是一门生物医学学科，使用 描述生物系统、疾病过程和疾病之间相互作用的数学计算机模型 药理学，在各种情况下使药物治疗个体化。K23机制将使 我要在我的基本药理学技能的基础上，继续进行这一高级培训，这对开发 基于生理学的药代动力学和药效学(PBPK/PD)模型 预测胃肠道疾病儿童的药物剂量浓度反应关系， 从肥胖儿童的PPI剂量开始，他们受到GERD的影响不成比例。检验……的有效性 我开发的PBPK/PD模型，我将需要设计、实施和有效地领导未来的纵向 临床试验，这是K23给我提供的一个指导研究的机会。将我的模型扩展到其他 儿童常用的药物，我还需要更新我的药物代谢知识库 在我的教育计划中提出的超越CYP2C19的酶。作为一名儿科胃肠病专家和临床医生 CMH的药理学家，有75%的受保护研究时间，一个由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领导的教职员工，药学博士，我有必要的机构 支持、血统和学术环境以实现本文件中所述的研究和培训目标 K23应用程序。 好了！

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. !