SOFT TISSUE PENETRATION OF ERTAPENEM

厄他培南的软组织渗透

• 批准号: 7374684
• 负责人: HARTMUT DERENDORF
• 金额: $ 3.37万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374684
• 关键词: SOFT; TISSUE; PENETRATION; ERTAPENEM

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。儿童肥胖症在发展中国家和发达国家都越来越普遍。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岁青少年的超重率增加了两倍（1）。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个体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用于治疗急性下呼吸道和腹腔内感染的抗生素药物。厄他培南也被批准用于治疗软组织感染，但目前尚不清楚其体内渗透到人体骨骼肌和皮下脂肪组织的间隙中。由于缺乏直接测量组织渗透的适当方法，因此批准主要基于血浆浓度数据，而不是实际靶组织浓度。然而，组织浓度的测量以及随后靶位点浓度与对治疗的药效学反应的关联是至关重要的，尤其是对于具有高血浆蛋白结合的药物，如厄他培南。基于靶部位的未结合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量厄他培南给药后软组织暴露于未结合药物浓度的情况。为此，我们将采用体内微透析技术，一种创新的生物分析采样技术，测量静脉注射1 g厄他培南后，厄他培南在血浆和骨骼肌组织间隙中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、研究者发起的初步试验在3名健康志愿者中进行初步体内实验，并在6名健康志愿者中进行（主研究）。结果变量为Cmax-组织、AUC组织、tmax-组织、C组织-MIC比值、AUC组织/AUC血浆比值，作为厄他培南的血浆-组织渗透的量度。