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基于组织穿透性的群体药物动力学模型及计算机仿真技术在抗菌药物临床给药方案优化中的应用
中文摘要

抗菌药物作为对人类健康至关重要的药物,主要通过杀灭或抑制入侵到机体的外来病原菌而发挥作用,其疗效跟抗菌药物本身、病原菌和受感染的机体三者均有关系,是三者之间相互作用的结果。抗菌药物的药物动力学和药效学相结合可全面描述抗菌药物在机体内杀灭病原菌的过程。根据其药物动力学/药效学(PK/PD)特性可以将抗菌药物分为:时间依赖性抗菌药物、浓度依赖性抗菌药物和同时具有浓度依赖性和时间依赖性的抗菌药物三类。在制定抗菌药物的给药方案时,从其PK/PD特性出发是抗菌药物合理应用的重点,此概念也被写入了国家卫生计生委、国家中医药管理局、解放军总后勤部原卫生部在2015年7月印发的《抗菌药物临床应用指导原则(2015年版)》中,在全国范围内被广泛学习、讨论并贯彻。 传统的药物动力学(Pharmacokinetics,PK)研究需要在目标人群中进行密集血液采样,存在患者依从性差,采样不易等缺点。群体药物动力学(Population Pharmacokinetics,pop PK,PPK)是解决此问题的有效手段。然而经典的PK和PPK研究均只局限于药物在血中的浓度,对于组织体液内的药物浓度,都只用虚拟抽象的外周室、深外周室等表示,无法准确反应药物在各组织体液,尤其是感染病变组织体液内的浓度。不难理解,药物对细菌的作用是发生在感染部位的,因此,除血流感染外,相比于是否能维持抗菌药物在血中的浓度,抗菌药物在感染部位能否达到并维持有效的抗菌浓度才是抗菌药物合理应用的关键。 组织药物动力学(Tissue PK)是近年来兴起的用来表征药物在组织或体液中浓度随时间变化过程的研究方法,国际上已有专家和学者对此展开深入研究。 Tissue PK也成为了目前国际上抗菌药物在感染部位药物浓度变化研究的前沿、热点和难点。但是由于组织体液中生物样本比血液样本更难获得,这类已发表的研究大多数为动物实验或非常有限数量(通常少于10名)病人中的点对点的组织穿透性试验,未能反映药物浓度在组织体内的随时间变化的整个过程,为临床提供的信息极其有限。为解决这一难题,将PPK的研究方法引入Tissue PK,通过对稀疏采样得到的组织体液浓度数据进行拟合是解决采样难题的有效方法。本课题创新性、探索性地将群体药物动力学的研究方法引入抗菌药物在组织体液中的动力学过程描述,并通过在PPK模型中建立拟生理室,同时考虑抗菌药物在血浆及感染部位组织中的浓度,首先建立了基于组织穿透性的美罗培南和左氧氟沙星类生理群体药物动力学模型,然后根据此模型结合蒙特卡洛模拟法仿真药物在血及组织体液中的浓度随时间变化经时过程结果并进行PK/PD分析,提出该两种药物在不同适应证患者群体中基于感染部位达到杀灭目标病原菌不同敏感性程度(MIC水平)情况下有效抗菌治疗方案。对于难治的对美罗培南等碳青霉烯类药物耐药的鲍曼不动杆菌引起的感染,本课题也对现有含有或不含有多黏菌素的联合用药方案进行了系统性综述和荟萃分析,为本课题组下一步即将开展的基于组织穿透性的联合用药研究进行了方案筛选。最后对提出的左氧氟沙星给药方案进行了外部临床研究结果验证,进一步确定了左氧氟沙星的优化临床给药方案。 本研究共分为四个部分。第一部分针对医院获得性耐多药鲍曼不动杆菌等革兰阴性菌引起的脑膜炎,根据美国、欧洲和我国指南的推荐首选药物时间依赖性抗菌药物美罗培南作为研究药物,开展了基于美罗培南脑脊液/血清组织体液的PPK及PK/PD研究,并据此提出了该药单药治疗细菌性脑膜炎的优化给药方案;第二部分针对临床上出现美罗培南等碳青霉烯类耐药的鲍曼不动杆菌引起的感染病例日益增多现状,采用系统性综述及荟萃分析的方法评估以多黏菌素为基础的治疗方案是否优于不含多黏菌素的替代方案,为本课题组今后开展基于联合用药的组织穿透性研究进行方案筛选;第三部分针对以肺炎链球菌为主的革兰阳性菌引起的社区获得性肺炎(community acquired pneumonia,CAP),同样选取了三个指南同时推荐的浓度依赖性抗菌药物左氧氟沙星作为研究药物,开展该药在肺组织、肺粘膜及肺上皮细胞衬液/血清中PPK及PK/PD研究,系统性分析该药在各肺组织体液穿透率,并据此提出了该药治疗CAP优化给药方案;第四部分通过本课题组之前完成的左氧氟沙星多中心、前瞻性CAP临床试验数据,对第三部分建立的基于肺组织体液穿透性的PPK模型外推的准确性及有效性进行评估,并对第三部分左氧氟沙星PK/PD结果予以临床验证,确立该给药方案有效性。本研究选择了目前临床门诊常用药物和危重感染的药物为代表,为该类药物临床合理应用策略提供询证医学的依据。本课题提出的基于组织穿透性的定量模拟-临床验证的研究思路及研究方法属探索性研究,以期在此前沿领域建立一套严谨可靠实用的方法,并抛砖引玉,期待引起抗感染领域学术界关注,让更多学者投入这一研究方向,共同推进优化抗菌药物治疗方案,提高该类药物临床有效性,降低细菌耐药性产生的几率。

英文摘要

Antimicrobial agentsachieved their pharmacological effects by inhibiting or killing organisms which entered in to the body, and their efficacy is based on the interactons among the organism, the drug and the host. According to their PK/PD properties, antimicrobial agents can be categorized to be time-dependant antimicrobial agents, concentration-dependant antimicrobial agents and both time- and concentration-dependant antimicrobial agents. Optimizing treatment regimen of antimicrobial agents according to their PK/PD profiles were included in the most updated Chinese National Guidelines on Clinical Use of Antimicrobial Agents (2015) and is attracting more and more attention. The methodology and approach of classis pharmacokinetics (PK) research requires intensive PK sampling which often results in poor compliance and inconvenient arrangements, thus, population pharmacokinetics (pop PK, PPK) was introduced to allow sparse sampling. However, previous PPK studies focused on plasma or serum drug concentration only, with the major limitation of lacking of information of drug concentration at sides where infections occur. Except bloodstream infections, the concentration of antimicrobial agents at infection sides is more important, and the research of concentration v.s. time profile in tissue is called tissue PK. Compared to blood samples, tissue samples are much more difficult to obtain. Tissue penetration based PPK and PK/PD analyses can provide solution for these objectives. This innovative study explored a new way of PPK research and treatment regimen optimization. Specific tissue compartments were introduced into PPK models to reflect drug concentration v.s. time change at sides of infections. Plasma and tissue PK were linked by transfer multipliers in PPK models built by NONMEM software V7.3. Virtual patients’ data by Monte Carlo Simulations were used to calculate probability of target attainment (PTA) to recommend optimized treatment regimens. This study was divided into four parts: Part One focused on hospital acquired infections, and the model drug is meropenem, a time-dependant antimicrobial agent; Part Two focused on a systematic review and meta analysis on polymyxins versus alternative antibiotics against carbapenem-resistant Acinetobacter baumannii; Part Three focused oncommunity acquired infections, and the model drug islevofloxacin, a concentration-dependant antimicrobial agent; Part Fourincluded four external levofloxacin clinical trials, including one single dose and multiple dose PK study, one abosulute bioequivalence study, one PPK study in community acquired lower respiratory infection paitents, and one open label, multicenter, parallel clinical study on levofloxacin to treat community acquired lower respiratory infection and urinary tract infection patients. The choices of diseases and drugs can cover research needs and can provide clues and direction for future researches.

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