SOFT TISSUE PENETRATION OF ERTAPENEM

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。儿童肥胖症在发展中国家和发达国家都变得越来越普遍。在美国，在过去的20年里，6-11岁儿童的超重率增加了一倍，12-17岁的青少年超重率增加了两倍。肥胖与胰岛素抵抗相关，并通过增加2型糖尿病(2)、血脂异常和高血压的风险而促进动脉粥样硬化的进展，所有这些都是心血管疾病的危险因素。因此，肥胖对儿童时期肥胖的长期影响可能会产生深远的后果。厄他培南是一种公认的抗生素药物，用于治疗急性下呼吸道和腹内感染。厄他培南也被批准用于软组织感染的治疗，但它在人体内对骨骼肌和皮下脂肪组织间质的渗透性目前尚不清楚。由于缺乏直接测量组织渗透的适当方法，批准主要基于血浆浓度数据，而不是实际的目标组织浓度。然而，测量组织浓度并随后将靶部位浓度与治疗的药效学反应相关联是至关重要的，特别是对于具有高血浆蛋白结合的药物，如厄他培南。基于靶部位的游离药物浓度与抗菌治疗的成功直接相关这一概念，我们将在本研究中确定健康志愿者体内单剂厄他培南后软组织对游离药物浓度的暴露情况。为此，我们将采用体内微透析这一创新的生物分析采样技术来测量静脉注射后厄他培南在血浆和骨骼肌组织间隙中的时间与自由浓度曲线。给药1克。这项研究将以非对照、开放标签、调查者发起的先导试验的形式在3名健康志愿者进行体内试验，并在6名健康志愿者(主要研究)中进行。结果变量为Cmax组织、AUC组织、Tmax组织、COrganization-MIC比率、AUC组织/AUC血浆比率，以此来衡量厄他培南的血浆-组织渗透。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Childhood obesity has become increasingly prevalent in both developing and developed countries. In the United States, the prevalence of being overweight has doubled in 6-11 year old children and tripled in 12-17 year old adolescents in the last 20 years (1). Obesity is associated with insulin resistance and promotes the progression of atherosclerosis by increasing the risk of type 2 diabetes (2), dyslipidemia, and hypertension, all of which are risk factors for cardiovascular disease. Hence, the long-term impact of obesity on individuals developing obesity as children may have profound consequences. Ertapenem is an established antibiotic drug for the therapy of acute lower respiratory tract and intra-abdominal infections. Ertapenem is also approved for the treatment of soft tissue infections, but its in vivo penetration into the interstitial space of skeletal muscle and subcutaneous adipose tissue in humans is presently unknown. As there is a lack of appropriate methods to directly measure tissue penetration, approval is based mainly on plasma concentration data rather than actual target tissue concentrations. Measurement of tissue concentrations and subsequent association of target site concentrations with the pharmacodynamic response to treatment, however, is crucial especially for drugs with a high plasma protein binding such as ertapenem. Based on the concept that the unbound drug concentration at the target site is directly correlated with the success of antimicrobial therapy, we will set out in the present study to determine soft tissue exposure to unbound drug concentrations following administration of a single dose ertapenem in vivo in healthy volunteers. For this purpose we will employ in vivo microdialysis an innovative bioanalytical sampling technique to measure the time versus unbound concentration profiles of ertapenem in plasma and in the interstitial space of skeletal muscle tissue following i.v. administration of 1g of the drug. The study will be carried out as a non-controlled, open-label, investigator initiated pilot trial in 3 healthy volunteers for the pilot in vivo experiments and in 6 healthy volunteers (Main study). The outcome variables are the Cmax-tissue, AUCtissue, tmax-tissue, Ctissue -MIC ratios, AUCtissue / AUCplasma ratios, as a measure of the plasma-tissue penetration of ertapenem.