Creating PK/PD models for oxytocin action in humans and bridging to intranasal delivery

创建人体催产素作用的 PK/PD 模型并桥接鼻内递送

基本信息

批准号：
10332265
负责人：
James Eisenach
金额：
$ 33.3万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10332265
关键词：
Acute Acute Pain Affect Affective Age Animals Area Arthritis Biological Biological Assay Biological Markers Brain Caliber Childbirth Clinic Clinical Clinical Research Clinical Trials Complex Conflict (Psychology)Contracts Controlled Clinical Trials Cross-Over Studies Data Dimensions Discipline of obstetrics Disease Dose Double-Blind Method Drug Kinetics Eligibility Determination Enzyme-Linked Immunosorbent Assay Ethnic Origin Fiber Foundations Frequencies Functional disorder Funding Future Grant Human Injury International Intranasal Administration Intravenous infusion procedures Knee Knowledge Laboratories Light Maps Measures Mechanoreceptors Methods Modeling Nerve Nervous system structure Neuraxis Neurohormones Nociception Nociceptors Operative Surgical Procedures Outcome Measure Oxytocin Pain Pathology Patients Penetration Perception Peripheral Persons Pharmacodynamics Pharmacology Placebo Control Plasma Pregnant Uterus Productivity Protocols documentation Psychophysics Pupil Race Randomized Recovery Reporting Research Rodent Route Self Administration Sensory Series Site Speed Stimulus Sweden Testing Time Touch sensation Translating Validation Weight Woman Work absorption appropriate dose base chronic pain clinical pain cognitive neuroscience desensitization disability drug action experimental study heat stimulus individual patient injury recovery intravenous injection knee replacement arthroplasty liquid chromatography mass spectrometry men nervous system disorder novel pain reduction pain relief pharmacodynamic model pharmacokinetic model postoperative recovery pre-clinical pressure protective effect sex simulation social neuroscience tool vibration volunteer

项目摘要

Project 3 Summary Surgery benefits most patients, but for some, it results in chronic pain and disability. Under current funding, we have moved the state of research in this area forward by developing and applying methods to more precisely map the speed of recovery in individual patients after surgery. In addition, we have shown that recovery after surgery in animals and humans is quicker if surgery occurs around the time of delivery, and this hastened recovery reflects oxytocin (OXT) actions. Although OXT’s effects on multiple neurologic disorders have been probed in animals, translational testing in humans is hampered by a route of administration (intranasal [i.n.]) with undetermined distribution in the brain or the periphery. Project 3 will build on these observations and translate, with guidance by Projects 1 and 2 and support by the PK/PD Core, critical testing of OXT’s actions on somatosensation and the sensory and affective dimensions of pain. Specifically: Aim 1. Create PK models of OXT in plasma after IV and i.n. administration and test covariates This Aim will determine oxytocin pharmacokinetics (PK) after IV and i.n. administration in plasma and test whether key biologic variables (sex, age, weight, race, ethnicity) affect this disposition. These data will be used to determine appropriate dosing to target sites of peripheral or central drug action, including pain relief. Aim 2: Define OXT actions at peripheral sites of somatosensation Using either pain report from a 5 minute heat stimulus or paradigms to be tested by our Swedish collaborators (under their funding by the Wallenberg Foundation outside this P01), we will create and validate a PK/PD (pharmacodynamic) model for OXT on somatosensation including pain in the periphery. This model will guide OXT dosing under a subaward in Sweden to directly test the effects of OXT on sensory afferents using microneurographic recording and by us to test the effects of OXT on light touch as well as pain fibers. Aim 3: Validate hippus as a measure of OXT action and bridge IV studies to intranasal administration We will for the first time establish a PK/PD model for oxytocin in the brain, using pupil diameter oscillations (hippus) as an outcome measure. We will then apply knowledge from Aims 1 and 2 to create PK/PD models for pain relief and central nervous system action after i.n. OXT administration. These models will guide dosing for future clinical trials of i.n. OXT to treat pain and other neurologic disorders.

项目3总结手术对大多数患者有益，但对某些患者来说，它会导致慢性疼痛和残疾。资金，我们通过开发和应用方法推动了该领域的研究状况更精确地绘制个体患者手术后的恢复速度此外，我们还表明了这一点。如果手术在分娩前后进行，动物和人类手术后的恢复会更快，并且这加速恢复反映了催产素 (OXT) 的作用，尽管 OXT 对多种神经系统疾病有作用。已在动物身上进行了探索，但人类的转化测试受到给药途径的阻碍（鼻内 [i.n.]）在大脑或外周中的分布尚未确定，项目 3 将以此为基础。观察和翻译，在项目 1 和 2 的指导下并得到 PK/PD 核心的支持，关键测试 OXT 对躯体感觉以及疼痛的感觉和情感维度的作用具体如下：目标 1. 创建 IV 和 i.n 给药后血浆中的 PK 模型并测试协变量。该目的将确定静脉注射和注射后血浆和注射后催产素的药代动力学 (PK)。测试关键的生物变量（性别、年龄、体重、种族、民族）是否会影响这些数据。用于确定外周或中枢药物作用靶位点的适当剂量，包括缓解疼痛。目标 2：定义 OXT 在体感外周部位的作用使用 5 分钟热刺激的疼痛报告或瑞典测试的范例合作者（在 P01 之外的 Wallenberg 基金会的资助下），我们将创建并验证 OXT 体感的 PK/PD（药效学）模型，包括外周疼痛。在瑞典的一项子奖项下指导 OXT 剂量，以使用以下方法直接测试 OXT 对感觉传入的影响显微神经影像记录并由我们测试 OXT 对轻触和疼痛纤维的影响。目标 3：验证 hippus 作为 OXT 作用的衡量标准，并将 IV 研究与鼻内给药联系起来我们将首次利用瞳孔直径建立大脑中催产素的PK/PD模型然后，我们将应用目标 1 和 2 中的知识来创建振荡（hippus）。 OXT 给药后用于缓解疼痛和中枢神经系统作用的 PK/PD 模型。将指导未来 OXT 治疗疼痛和其他神经系统疾病的临床试验的剂量。