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: 8645724
• 负责人: Athena F. Zuppa
• 金额: $ 40.88万
• 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/8645724
• 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.

描述（由申请人提供）：在儿科重症监护病房中更频繁地使用治疗性体温过低，并在儿科心脏骤停的情况下进行了研究。心脏骤停后，多个器官功能障碍综合征（MOD），尤其是肾功能障碍和肝功能障碍，很常见，会影响药物的代谢和排泄。此外，关于体温过低对孩子的能力的影响知之甚少 代谢药物。在体温过低的情况下，可能需要调整剂量调整，以避免药物的剂量不足和过度剂量。镇静剂和阿片类药物的剂量和药物积累不当会恶化现有的神经系统，循环和呼吸衰竭。人体实际药物和代谢物浓度的测量（药代动力学）提供了有关儿童如何代谢药物的信息。此外，给予不同儿童剂量后，这些浓度的变异性可能是由于药物代谢系统（药物遗传学）的遗传驱动差异而导致的。最后，这些遗传差异可能对体温过低有不同的反应。父母R01，“小儿心脏骤停后的治疗性低温下降”，比较了治疗性Normothermia vs.体温过低以改善神经系统生存的功效，这为研究器官衰竭，药物遗传学和体温过低对代谢性，清除和清除和药物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也将受到温度管理的影响，即使考虑到可能混淆器官功能障碍和遗传差异的可量化因子。该辅助R01应用的目标，低温对药理学（HIP）的影响是1）确定心脏骤停后的器官功能障碍对吗啡和米达唑胺药代动力学的影响在经历心脏骤停的孩子中。复杂的建模和仿真技术将用于检查与危害疾病，药物处置，药物遗传学和温度调节相关的生理学高度动态变化。将实施使用这种方法创建的模型，以优化对这些重症儿童的预期治疗。