Pharmacokinetics/Pharmacodynamics Core

药代动力学/药效学核心

• 批准号: 10609947
• 负责人: Steven Shafer
• 金额: $ 8.27万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609947
• 关键词: Acute; Acute Pain; Age; Animals; Behavior; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Central Nervous System; Clinical; Clinical Trials; Collaborations; Complex; Data; Disease; Dose; Drug Kinetics; Ensure; Equation; Goals; Human; Injury; Intramuscular; Kinetics; Measurement; Measures; Modeling; Modification; Nervous System; Nociception; Operative Surgical Procedures; Outcome Measure; Oxytocin; Pain; Pain Measurement; Patient Care; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Rattus; Recovery; Regimen; Reproducibility; Research; Research Personnel; Role; Route; Sensory; Serum; Site; Speed; Therapeutic; Time; Tissues; Translations; Weight; Work; chronic pain; clinical effect; clinical translation; design; drug action; healing; human subject; mathematical model; neurophysiology; pain reduction; pharmacodynamic model; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacologic; programs; response; sex; subcutaneous; tissue injury; uptake

PK/PD Core Summary The overall aims of this integrated P01 proposal are to advance fundamental understanding and provide clinical translation of oxytocin’s actions in the periphery and in the central nervous system as they relate to sensory processing and recovery from tissue injury, including surgery. The three goals of this program project are 1) to determine oxytocin pharmacokinetics (relationship between dose and concentration) and pharmacodynamics (relationship between concentration and drug effect) in rats and humans, 2) characterize the mechanisms of oxytocin actions on acute pain and sensitization at peripheral and central sites, and 3) determine the central and peripheral actions of oxytocin on recovery after tissue injury (e.g., surgery). Each of these goals is predicated on precise measurement of oxytocin dose and concentration, construction of mathematical models relating blood oxytocin concentration to oxytocin dose and route of delivery, and construction of mathematical models relating oxytocin concentration to drug effect. The first goal comprises measuring oxytocin dose, concentration, and effect, and developing mathematical models of these fundamental relationships. This is the critical analysis that brings new scientific rigor to the second and third aims, because we will use the pharmacokinetic and pharmacodynamic models to give oxytocin in a manner that facilitates rigorous exploration of the dose – concentration – drug response relationship for both acute pain and sensitization (goal 2) and speed of recovery (goal 3) for both peripheral and central sites (differentiated by leveraging differences in peripheral and central pharmacokinetics to target each site experimentally).

PK/PD核心摘要 这一综合P01提案的总体目标是促进基本理解和 提供催产素在外周和中枢神经系统中的作用的临床翻译 与感觉处理和从组织损伤中恢复有关，包括手术。 本项目的三个目标是：1)测定催产素的药代动力学(关系 剂量和浓度之间)和药效学(浓度和药效之间的关系) 在大鼠和人类中，2)描述了催产素对急性疼痛和敏化的作用机制 外周和中枢部位，以及3)确定催产素在恢复后的中枢和外周作用 组织损伤(例如，手术)。这些目标中的每一个都建立在催产素剂量和 建立了血催产素浓度与催产素剂量之间的数学模型 给药途径，建立催产素浓度与药物效应之间的数学模型。这个 第一个目标是测量催产素的剂量、浓度和效果，并建立数学模型 这些基本关系。这是批判性的分析，为第二和 第三个目的，因为我们将使用药代动力学和药效学模型在 以便于严格探索两者的剂量-浓度-药物反应关系的方式 外周和中心部位的急性疼痛和敏感化(目标2)和恢复速度(目标3) (通过利用外周和中枢药代动力学的差异来针对每个部位进行区分 实验中)。