Evaluating predictive methods and product performance in Healthy Adults for Pediatric Patients, Case Study: Furosemide
评估儿科患者在健康成人中的预测方法和产品性能,案例研究:呋塞米
基本信息
- 批准号:9331050
- 负责人:
- 金额:$ 15.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-15 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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.
这项提案的总体目标是探索体内给药模式,并暴露
速尿片剂中的速尿与水、牛奶、婴儿配方奶粉一起服用,确保健康
成年志愿者在与给药和喂食条件相似的情况下,进行通宵禁食
在儿科病人身上。重要的是,低溶解度药物在药典中很常见。体外探索性
药物评估和研究中心(CDER)最近的研究表明,
难溶药物的溶解性,从而潜在的生物利用度可能会在
存在儿童常用的液体,如牛奶或婴儿配方奶粉。然而,
这些给药液对药物生物利用度的影响需要在人体上进行验证。速尿,这是
生物制药分类系统(BCS)IV类(低溶解度,低渗透性),是一种模式药物
确定这些体外结果是否会转化为生物利用度的提高。
除了它作为模特的地位
药物,速尿是一种常用药物,也是治疗水肿症的基石
条件。由于生物利用度低而导致的治疗失败被认为是速尿的常见问题。
因此,给药液对速尿分子药代动力学(Pk)影响的表征具有
对人类疾病有很大影响的潜力。除了速尿的PK限制外,还有一个
速尿PK与药效学(PD)的复杂关系。值得注意的是,由于门槛
和剂量反应曲线的上限部分,总生物利用度的积极变化不一定
如果吸收速度减慢,峰值浓度降低,就会转化为更好的药物疗效。因此,
了解PK参数变化对PD参数的影响将是解释PK参数的关键
建议的速尿PK研究结果。
在目前的应用中,我们提出了一项随机4向交叉的正常受试者研究
速尿20毫克片剂与水,牛奶,婴儿配方奶粉,或确保加。这项研究将
包括在8名正常志愿者中进行细致的36小时住院患者生物样本收集方案,并创建
所产生的生物标本的生物储存库。此外,速尿在人体内的血药浓度测定
血浆和尿液中的钠排出量(PD对环状利尿剂的反应),体外溶解度,
溶解和蛋白质结合实验,然后是在体外,在硅胶和体内的综合方法
介绍了PK模型、基于生理的PK模型和PD模型的发展。通过多重PI计划,这
申请程序充分利用了美国国立卫生研究院资助的个人研究项目的丰富经验,包括
环状利尿剂给药后的临床生物样品收集以及体外和体内实验
Testani博士和Prasad博士的建模方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bhagwat Prasad其他文献
Bhagwat Prasad的其他文献
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{{ truncateString('Bhagwat Prasad', 18)}}的其他基金
PBPK prediction of ontogeny mediated alteration in hepatic drug elimination
个体发育介导的肝脏药物消除改变的 PBPK 预测
- 批准号:
8912821 - 财政年份:2015
- 资助金额:
$ 15.77万 - 项目类别:
PBPK prediction of ontogeny mediated alteration in hepatic drug elimination
个体发育介导的肝脏药物消除改变的 PBPK 预测
- 批准号:
9210642 - 财政年份:2015
- 资助金额:
$ 15.77万 - 项目类别:
PBPK prediction of ontogeny mediated alteration in hepatic drug elimination
个体发育介导的肝脏药物消除改变的 PBPK 预测
- 批准号:
10012580 - 财政年份:2015
- 资助金额:
$ 15.77万 - 项目类别:
PBPK prediction of ontogeny mediated alteration in hepatic drug elimination
个体发育介导的肝脏药物消除改变的 PBPK 预测
- 批准号:
9035414 - 财政年份:2015
- 资助金额:
$ 15.77万 - 项目类别:
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