Evaluating predictive methods and product performance in Healthy Adults for Pediatric Patients, Case Study: Furosemide

该提案的总体目标是探索体内递送模式和暴露于 当与水、牛奶、婴儿配方奶粉和Ensure Plus一起服用时， 在与给药和喂养条件相似的条件下，禁食过夜的成年志愿者 在儿科患者中。重要的是，低溶解度药物在药典中很常见。探索性体外 药物评价和研究中心（CDER）最近的研究表明， 溶解性差的药物的溶解度以及因此潜在的生物利用度可以在 存在通常用于儿童给药的液体，如牛奶或婴儿配方奶粉。然而，在这方面， 这些给药液体对药物生物利用度的影响需要在人体中验证。呋塞米， 生物药剂学分类系统（BCS）IV类（低溶解度，低渗透性），是一种模型药物， 确定这些体外结果是否会转化为改善的生物利用度。 除了作为模特的地位 药物，速尿是一种常用的药物和基石，医疗水肿 条件由于生物利用度差而导致的治疗失败被认为是呋塞米的常见问题。 因此，给药液体对呋塞米分子的药代动力学（PK）的影响的表征具有以下意义： 对人类疾病有很大的影响。除了呋塞米的PK限制外， 呋塞米PK和药效学（PD）之间的复杂关系。特别是，由于阈值 和剂量反应曲线的上限部分，总生物利用度的正变化可能不一定 如果吸收减慢并且峰浓度降低，则转化为改善的药物功效。因此，在本发明中， 了解PK参数变化对PD参数的影响对于解释 拟定的呋塞米PK研究结果。 在本申请中，我们提出了一项随机4向交叉正常受试者研究， 呋塞米20 mg片剂与水、牛奶、婴儿配方奶粉或Ensure Plus联合给药。这项研究将 包括在8名正常志愿者中进行细致的36小时住院生物标本收集方案， 生成的生物标本的生物储存库。此外，测定呋塞米浓度， 血浆和尿液以及尿钠排出量（对袢利尿剂的PD反应），体外溶解度， 溶出度和蛋白结合实验，然后是体外、计算机模拟和体内整合方法， 介绍了药代动力学、基于生理学的药代动力学和PD模型的发展。通过多个PI计划， 应用程序利用了个人PI的NIH资助的研究计划的丰富经验， 袢利尿剂给药后的临床生物标本收集以及体外和体内实验和 Testani博士和Prasad博士的建模方法。

The overarching goal of this proposal is to explore the in vivo delivery pattern, and exposure of furosemide from furosemide tablets when given with water, milk, baby formula and Ensure Plus to healthy adult volunteers following an overnight fast, under conditions that are similar to dosing and feeding conditions in pediatric patients. Importantly, low solubility drugs are common in the pharmacopeia. Exploratory in vitro studies by the Center for Drug Evaluation and Research (CDER) have recently demonstrated that the solubility, and thus potentially the bioavailability, of poorly soluble drugs may be highly enhanced in the presence of liquids commonly used to dose medications in children, such as milk or baby formula. However, the effect of these dosing liquids on bioavailability of drugs needs validation in humans. Furosemide, which is Biopharmaceutics Classification System (BCS) class IV (low solubility, low permeability), is a model drug to determine if these in vitro results will translate to improved bioavailability. In addition to its status as a model drug, furosemide is a commonly used medication and the cornerstone of medical treatment for edematous conditions. Treatment failure due to poor bioavailability is thought to be common problem with furosemide. Thus, the characterization of effect of the dosing liquids on pharmacokinetic (PK) of furosemide molecule has substantial potential to impact human disease. In addition to the PK limitations of furosemide, there is a complex relationship between PK and pharmacodynamics (PD) with furosemide. Notably, due to threshold and ceiling portions of the dose response curve, positive changes in total bioavailability may not necessarily translate into improved drug efficacy if absorption is slowed and peak concentrations are reduced. As such, understanding the effect of changes in PK parameters on PD parameters will be critical in interpreting the results of the proposed PK study of furosemide. In the current application, we propose a randomized 4-way crossover normal subjects study of furosemide 20mg tablets with co-administration of water, milk, baby formula, or Ensure Plus. The study will involve a meticulous 36-hour inpatient biospecimen collection protocol in 8 normal volunteers and creation of a biorepository of the generated biospecimens. Furthermore, determination of furosemide concentrations in plasma and urine in addition to urinary sodium output (the PD response to loop diuretics), in-vitro solubility, dissolution, and protein binding experiments, followed by an integrated in vitro, in silico and in vivo approach to the development of PK, physiology based PK and PD models are proposed. Through a multiple PI plan, this application leverages the substantial experience of the individual PI's NIH funded research programs involving clinical biospecimen collection following loop diuretic administration and in vitro and in vivo experiments and modeling approaches of Dr. Testani and Dr. Prasad respectively.