Impact of Hypothermia on Midazolam and Morphine Pharmacokinetics

低温对咪达唑仑和吗啡药代动力学的影响

• 批准号: 8339217
• 负责人: Athena F. Zuppa
• 金额: $ 43.08万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8339217
• 关键词: Accounting; Affect; Age; CYP3A4 gene; Child; Childhood; Clinical; Coma; Complex; Critical Illness; Critically ill children; Data; Dose; Drug Kinetics; Drug usage; Excretory function; Functional disorder; Future; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Glucuronides; Glucuronosyltransferase; Goals; Heart Arrest; Hepatic; Kidney; Knowledge; Measurement; Metabolic Pathway; Metabolism; Midazolam; Modeling; Morphine; Multiple Organ Failure; Neurologic; Neurological outcome; Opiates; Organ; Organ Weight; Organ failure; Parents; Pediatric Intensive Care Units; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Pharmacotherapy; Physiological; Physiology; Publishing; Research; Research Infrastructure; Respiratory Failure; Resuscitation; System; Techniques; Temperature; Therapeutic; Uridine Diphosphate; Work; base; comparative efficacy; design; drug clearance; drug metabolism; experience; improved; models and simulation; natural hypothermia; pharmacokinetic model; prospective; response; sedative

DESCRIPTION (provided by applicant): Therapeutic hypothermia is being used more frequently in the pediatric intensive care unit, and is being studied in the setting of pediatric cardiac arrest. Following cardiac arrest, multiple organ dysfunction syndrome (MODS), especially renal and hepatic dysfunction, is common and affects the metabolism and excretion of drugs. In addition, very little is known about the impact of hypothermia on a child's ability to metabolize medications. Dose adjustments may be required in the setting of hypothermia to avoid under-dosing and over- dosing of medications. Improper dosing and drug accumulation of sedatives and opiates can worsen existing neurologic, circulatory and respiratory failure. The measurement of the actual drug and metabolite concentrations in the body (pharmacokinetics) provides information on how a child metabolizes medications. In addition, variability in these concentrations after the administration of equal doses to different children may result from genetically driven differences in drug metabolizing systems (pharmacogenetics). Finally, these genetic differences may respond differently to hypothermia. The parent R01, "Therapeutic Hypothermia After Pediatric Cardiac Arrest", comparing the efficacy of therapeutic normothermia vs. hypothermia to improve neurologic survival provides a unique opportunity to study the impact of organ failure, pharmacogenetics and hypothermia on metabolism, clearance and drug disposition. Thus, our overarching hypothesis is that morphine and midazolam disposition will be affected by temperature management even when accounting for potentially confounding quantifiable factors of organ dysfunction and genetic differences. The objectives of this ancillary R01 application, Hypothermia's Impact on Pharmacology (HIP) are to 1) determine the impact of organ dysfunction following cardiac arrest on the pharmacokinetics of morphine and midazolam, 2) identify the impact of hypothermia on the pharmacokinetics of morphine and midazolam and 3) identify the influence of polymorphisms on drug metabolizing systems on the response to hypothermia in children who have experienced cardiac arrest. Sophisticated modeling and simulation techniques will be utilized to examine the highly dynamic changes in physiology associated with critical illness, drug disposition, pharmacogenetics and temperature modulation. The models created using this approach will be implemented to optimize the prospective treatment of these critically ill children. PUBLIC HEALTH RELEVANCE: This project will use sophisticated modeling and simulation techniques to evaluate the impact of genetics and temperature modulation, specifically hypothermia, on the pharmacokinetics of morphine and midazolam in children after cardiac arrest. Additional variables such as degree of illness, age, weight and organ dysfunction on will be examined. This proposed work will advance the understanding of the complex interaction between hypothermia and pharmacogenetics, and their impact on drug metabolism and overall disposition in critically ill children.

描述（由申请人提供）：治疗性低温在儿科重症监护室中使用得更频繁，并且正在研究儿科心脏骤停的情况。心脏骤停后，多器官功能障碍综合征（MODS），尤其是肝肾功能障碍是常见的，并影响药物的代谢和排泄。此外，人们对体温过低对儿童的能力的影响知之甚少， 代谢药物。在体温过低的情况下，可能需要调整剂量，以避免药物剂量不足和过量。镇静剂和阿片类药物的剂量不当和药物蓄积会使现有的神经、循环和呼吸衰竭恶化。测量体内的实际药物和代谢物浓度（药代动力学）提供了有关儿童如何代谢药物的信息。此外，不同儿童接受相同剂量给药后这些浓度的变异性可能是药物代谢系统（药物遗传学）的遗传差异所致。最后，这些遗传差异可能对体温过低有不同的反应。母研究R01，“儿科心脏骤停后的治疗性低温”，比较了治疗性常温与低温对改善神经系统生存的疗效，为研究器官衰竭、药物遗传学和低温对代谢、清除和药物处置的影响提供了独特的机会。因此，我们的总体假设是，吗啡和咪达唑仑的处置将受到温度管理的影响，即使考虑到器官功能障碍和遗传差异的潜在混淆量化因素。该辅助R01应用程序“低温对药理学的影响（HIP）”的目的是：1）确定心脏骤停后器官功能障碍对吗啡和咪达唑仑药代动力学的影响，2）确定低温对吗啡和咪达唑仑的药代动力学的影响，以及3）确定药物代谢系统多态性对经历过心脏骤停的儿童对低温反应的影响。将利用先进的建模和仿真技术来研究与危重病，药物处置，药物遗传学和温度调节相关的生理学的高度动态变化。使用这种方法创建的模型将被实施，以优化这些重症儿童的前瞻性治疗。 公共卫生关系：该项目将使用复杂的建模和模拟技术来评估遗传学和温度调节，特别是低温对儿童心脏骤停后吗啡和咪达唑仑的药代动力学的影响。将检查其他变量，如疾病程度、年龄、体重和器官功能障碍。这项拟议的工作将促进对低温和药物遗传学之间复杂相互作用的理解，以及它们对重症儿童药物代谢和整体处置的影响。