SOFT TISSUE PENETRATION OF ERTAPENEM

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。儿童肥胖在发展中国家和发达国家都日益普遍。在美国，在过去的20年里，6-11岁儿童超重的患病率翻了一番，12-17岁青少年超重的患病率翻了三倍(1)。肥胖与胰岛素抵抗有关，并通过增加2型糖尿病(2)、血脂异常和高血压的风险来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，肥胖对儿童肥胖的长期影响可能会产生深远的影响。厄他培南是治疗急性下呼吸道和腹腔感染的常用抗生素。厄他培南也被批准用于治疗软组织感染，但其在人体骨骼肌间质和皮下脂肪组织中的体内渗透目前尚不清楚。由于缺乏直接测量组织渗透的合适方法，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，测量组织浓度以及随后的靶点浓度与治疗的药效学反应的关联是至关重要的，特别是对于具有高血浆蛋白结合的药物，如厄他培南。基于目标部位的非结合药物浓度与抗菌治疗的成功直接相关的概念，我们将在本研究中确定健康志愿者体内单剂量厄他培南后软组织暴露于非结合药物浓度。为此，我们将采用体内微透析一种创新的生物分析取样技术来测量静脉注射1g药物后血浆和骨骼肌组织间质中厄他培南的时间与未结合浓度曲线。本研究将作为一项非对照、开放标签、研究者发起的先导试验进行，在3名健康志愿者中进行体内先导实验，在6名健康志愿者中进行（主要研究）。结果变量为Cmax-tissue， AUCtissue, tmax-tissue， Ctissue -MIC比率，AUCtissue / AUCplasma比率，作为厄他培南血浆组织渗透的量度。

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.