Elucidation of an informed drug dosing scheme to minimize kidney injury

阐明知情的药物剂量方案以尽量减少肾损伤

• 批准号: 8689284
• 负责人: Marc Howard Scheetz
• 金额: $ 45.88万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689284
• 关键词: Accounting; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse event; American; Animal Model; Animals; Antibiotics; Biological Markers; Bypass; Clinical; Clinical Research; Computer Simulation; Critical Care; Critical Illness; Data; Data Set; Dose; Dose Fractionation; Drug Evaluation; Drug Exposure; Drug Kinetics; Employment; Ensure; Etiology; Evaluation Research; Event; Frequencies; Future; Goals; Health; Histopathology; Human; In Vitro; Incidence; Individual; Infection; Injury; Intensive Care Units; Kidney; Laboratories; Laboratory Study; Lead; Link; Marketing; Measures; Methods; Metric; Mission; Modeling; Monte Carlo Method; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Population; Prevention; Probability; Public Health; Rattus; Regimen; Research; Safety; Scheme; Sepsis; Septic Shock; Shapes; Statistical Models; Target Populations; Techniques; Testing; Time; Toxic effect; United States; United States Food and Drug Administration; United States National Institutes of Health; Vancomycin; Variant; Vision; Work; animal data; base; clinical practice; clinical risk; cost; design; experience; flexibility; improved; mathematical model; mortality; novel; pharmacodynamic model; pharmacokinetic model; post-market; prototype; public health relevance; success

DESCRIPTION (provided by applicant): Approved drugs are rarely initially studied in "real-world" patients in a manner sufficient to adequately detail their toxicity profile. Thus, an opportunity exists to refine drug dosing schemes even after they are approved by the Food and Drug Administration. Advances in mathematical modeling techniques now allow design of dosing schemes that minimize toxicity in "real-world" patients after the drug exposure-toxicity relationship and the variability of drug exposure in the target population is known. Vancomycin is a prototype drug that is a cornerstone in the treatment of Gram positive infections and represents a preventable cause of Acute Kidney Injury (AKI). Owing to over 50 years of clinical experience, much is known about vancomycin pharmacokinetic (PK) exposure. However, the relationship with the pharmacodynamic (PD) outcome of AKI remains poorly defined. This project seeks as a long term goal to integrate data from validated PK/PD models (in vitro, animal, and human) and human PK studies to construct clinical drug dosing strategies that minimize the probability of antibiotic-exposure related adverse events while maximizing efficacy. The overall objective of this application is to employ vancomycin as a prototype drug that causes AKI to elucidate the PK/PD relationship and identify optimal dosing schemes. The central hypothesis of this research is that the intensity and shape of the vancomycin exposure profile accounts for the onset and the extent of AKI. Our hypothesis has been formulated from observations that AKI occurs with contemporary vancomycin dosing schemes in humans Recent animal studies confirm causality when humanized vancomycin exposures are used. This work expands upon previous clinical studies, in silico studies, and laboratory efforts, and employs well validated techniques to focus on the prevention of drug-induced AKI. Specifically, use of an animal toxicity model will allow for carefully planned permutations of vancomycin exposures and bypass the shortcomings of prior clinical analyses where PK/PD endpoints have not been discerned because of homogenous human dosing schemes. The rationale that underlies the proposed research is that the drug exposure-toxicity link must be clearly defined before optimal human regimens can be designed. This application will address two specific aims. In Aim #1, the vancomycin exposure profile that causes acute kidney injury will be determined by 1) employing carefully controlled dose-range and dose-fractionation studies in rats and 2) measuring AKI with novel biomarkers and traditional histopathology. In Aim #2, mathematical probability modeling will be conducted with Monte Carlo Simulations that incorporate 1) known vancomycin exposure variability in critical care patients and 2) identified thresholds for vancomycin induced AKI and 3) targets for vancomycin efficacy. We expect that the proposed work will lead to the outcome of vancomycin dosing schemes that minimize AKI while maximizing efficacy for "real-world" patients. This contribution is expected to be significan since optimizing drug therapies to avoid preventable adverse events is the first step to improving the safety of drugs already available in the market.

描述（由申请人提供）：批准的药物很少在“真实世界”患者中进行初步研究，以充分详细说明其毒性特征。因此，即使在食品和药物管理局批准之后，也存在改进药物给药方案的机会。数学建模技术的进步现在允许设计给药方案，在已知目标人群中药物暴露的药物安全性-毒性关系和变异性后，使“现实世界”患者的毒性最小化。万古霉素是一种原型药物，是治疗革兰氏阳性菌感染的基石，是急性肾损伤（阿基）的可预防原因。由于超过50年的临床经验，对万古霉素药代动力学（PK）暴露有很多了解。然而，与阿基的药效学（PD）结局的关系仍然不明确。本项目的长期目标是整合来自经验证的PK/PD模型（体外、动物和人体）和人体PK研究的数据，以构建临床药物给药策略，最大限度地降低药物暴露相关不良事件的概率，同时最大限度地提高疗效。本申请的总体目标是采用万古霉素作为导致阿基的原型药物，以阐明PK/PD关系并确定最佳给药方案。本研究的中心假设是万古霉素暴露特征的强度和形状解释了阿基的发作和程度。我们的假设是根据观察结果制定的，即阿基在人类中与当代万古霉素给药方案发生。最近的动物研究证实了使用人源化万古霉素暴露时的因果关系。这项工作扩展了以前的临床研究，计算机模拟研究和实验室工作，并采用了经过充分验证的技术来重点预防药物诱导的阿基。具体而言，使用动物毒性模型将允许仔细计划万古霉素暴露的排列，并绕过既往临床分析的缺点，其中由于同质的人体给药方案，PK/PD终点尚未识别。这项研究的基本原理是，在设计出最佳的人类治疗方案之前，必须明确药物的安全性-毒性联系。本申请将针对两个具体目标。在目标1中，将通过1）在大鼠中采用仔细控制的剂量范围和剂量分级研究和2）使用新型生物标志物和传统组织病理学测量阿基来确定导致急性肾损伤的万古霉素暴露特征。在目标#2中，将使用蒙特卡罗模拟进行数学概率建模，其中包括1）重症监护患者中已知的万古霉素暴露变异性和2）万古霉素诱导阿基的确定阈值和3）万古霉素疗效的目标。我们预计，拟议的工作将导致万古霉素给药方案的结果，最大限度地减少阿基，同时最大限度地提高“现实世界”患者的疗效。这一贡献预计将是重要的，因为优化药物治疗以避免可预防的不良事件是提高市场上现有药物安全性的第一步。

项目成果

Resolution of acyclovir-associated neurotoxicity with the aid of improved clearance estimates using a Bayesian approach: A case report and review of the literature.

• DOI: 10.1111/jcpt.12520
• 发表时间: 2017-06
• 期刊: Journal of clinical pharmacy and therapeutics
• 影响因子: 2
• 作者: Watson WA;Rhodes NJ;Echenique IA;Angarone MP;Scheetz MH
• 通讯作者: Scheetz MH

Relationship between vancomycin exposure and outcomes among patients with MRSA bloodstream infections with vancomycin Etest® MIC values of 1.5mg/L: A pilot study.

万古霉素 Etest® MIC 值为 1.5mg/L 的 MRSA 血流感染患者的万古霉素暴露与结果之间的关系：一项试点研究。

• DOI: 10.1016/j.diagmicrobio.2017.03.008
• 发表时间: 2017
• 期刊: Diagnostic microbiology and infectious disease
• 影响因子: 2.9
• 作者: Martirosov,DM;Bidell,MR;Pai,MP;Scheetz,MH;Rosenkranz,SL;Lodise,TP
• 通讯作者: Lodise,TP

Relationship between day 1 and day 2 Vancomycin area under the curve values and emergence of heterogeneous Vancomycin-intermediate Staphylococcus aureus (hVISA) by Etest® macromethod among patients with MRSA bloodstream infections: a pilot study.

• DOI: 10.1186/s12879-017-2609-0
• 发表时间: 2017-08-02
• 期刊: BMC infectious diseases
• 影响因子: 3.7
• 作者: Martirosov DM;Bidell MR;Pai MP;Scheetz MH;Rosenkranz SL;Faragon C;Malik M;Mendes RE;Jones RN;McNutt LA;Lodise TP
• 通讯作者: Lodise TP

Correction for Rhodes et al., Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats.

对 Rhodes 等人的《万古霉素治疗大鼠急性肾损伤新型尿液生物标志物升高相关万古霉素暴露的评估》进行修正。

• DOI: 10.1128/aac.00185-17
• 发表时间: 2017
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Rhodes,NathanielJ;Prozialeck,WalterC;Lodise,ThomasP;Venkatesan,Natarajan;O'Donnell,JNicholas;Pais,Gwendolyn;Cluff,Cameron;Lamar,PeterC;Neely,MichaelN;Gulati,Anil;Scheetz,MarcH
• 通讯作者: Scheetz,MarcH