DDI-on-a-chip: an optimized liver microphysiological system and microenvironment for complex drug-drug interaction studies
DDI-on-a-chip:用于复杂药物相互作用研究的优化肝脏微生理系统和微环境
基本信息
- 批准号:10324897
- 负责人:
- 金额:$ 25.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-21 至 2023-03-20
- 项目状态:已结题
- 来源:
- 关键词:AdsorptionAffectBiological AssayCell Culture TechniquesCellsChemicalsClinicalComplexDataDecision MakingDevelopmentDrug CostsDrug ExposureDrug InteractionsDrug KineticsDrug ModelingsDrug toxicityElderlyEngineeringEnzyme InhibitionEnzymesEvaluationEventFee-for-Service PlansGene ExpressionGrowth FactorGuidelinesHealthHealthcareHepaticHepatocyteHospitalizationHumanIn VitroLeadLiverMetabolismModelingMorbidity - disease rateNutrientPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhasePhenotypePhysiologicalPhysiologyPolypharmacyPopulationPre-Clinical ModelPreclinical Drug DevelopmentPredictive ValuePrevalenceProcessPropertyRecommendationReproducibilityRiskSafetySignal TransductionSmall Business Innovation Research GrantSomatotropinSystemTechnologyTimeToxic effectTreatment EfficacyUnited StatesWithdrawaladverse drug reactionbaseclinical effectclinical predictorsclinically relevantcostcost effectivecost estimatedesigndrug developmentdrug metabolismexperimental studyfetalfirst-in-humanimprovedinterestmicrophysiology systemnovelnovel therapeuticsperpetratorspharmacokinetic modelpolycarbonatepre-clinicalpreventscreeningtranscription factor
项目摘要
Project Summary
Drug-drug interactions (DDIs), caused by the administration of multiple drugs simultaneously (i.e
polypharmacy), can lead to adverse drug reactions (ADRs). The prevalence of polypharmacy-related DDIs
among older adults is ~80%. DDI-related ADRs can cause profound clinical effects, either by reducing
therapeutic efficacy or increasing the toxicity of drugs. In the United States (US), ADRs are common, causing
1.1% of annual hospital admissions, and expensive with associated annual costs estimated between 30-180
billion dollars. Moreover, approximately 50% of the drugs withdrawn for safety reasons from the US market
between 1999 and 2003 were associated with DDIs. This is especially relevant for complex DDIs which include
metabolism-transporter interplay, time-dependent and mixed inhibition/induction of drug-metabolizing enzymes
(DMEs) and transporters, and metabolite-based inhibition/induction. As DDIs cannot be prevented without
comprehensive drug pharmacokinetic (PK) data to guide medication adjustments according to DDI risks, there
is a need for carefully planned preclinical and clinical DDI studies during drug development. However, current in
vitro preclinical liver PK models, including microphysiological systems (MPSs), suffer from important functional
limitations such as expression of a fetal phenotype, low expression levels of drug-metabolizing enzymes and
transporters, and rapid phenotypic dedifferentiation (i.e., short-term culture systems). This proposed technology
will be especially applicable for drugs with complex DDI liability including time-dependent induction of DMEs and
transporters.
Javelin’s overall strategy is to develop microphysiological systems (MPSs) optimized for drug metabolism
and pharmacokinetics (DMPK) studies including DDIs to be used in combination with our quantitative systems
pharmacology (QSP) models to generate more predictive preclinical drug data. This SBIR phase I project will
establish the optimal cellular and hepatotropic factor microenvironment to drive long-term, physiologically-
relevant expression, and activity of liver DMEs and transporters. The endogenous hepatotropic factors will be
selected for their ability to maintain liver cell health and drive the transcription factor signaling networks that
regulate DME and transporter gene expression. The hepatotropic factors will be screened using a high-
throughput fractional factorial analysis approach and optimized in Javelin’s polycarbonate (i.e., PDMS-free to
minimize nonspecific drug adsorption), millifluidic, recirculating MPS engineered for DMPK studies. The resulting
medium supplement, “DMPK-optimal” will be the first chemically-defined, xenoprotein-free supplement designed
to drive sustained DME and transporter gene expression and activity for DMPK-DDI studies. Javelin’s DMPK-
DDI platform will be provided as a low-cost, commercial-available product to pharmaceutical companies
interested in generating comprehensive, accurate, human-based PK data to better inform their drug development
process and design of first in-human (FIH) trials.
项目摘要
药物间相互作用(DDI),由多种药物同时给药(即
多药治疗),可导致药物不良反应(ADR)。多药相关DDI的患病率
在老年人中约为80%。DDI相关的ADR可能会导致严重的临床影响,无论是通过减少
治疗效果或增加药物的毒性。在美国,ADR很常见,
占每年住院人数的1.1%,费用昂贵,相关年度费用估计在30-180美元之间
亿美元此外,大约50%的药物因安全原因从美国市场撤回,
1999年至2003年与DDI有关。这对于复杂的DDI尤其重要,包括
代谢-转运蛋白相互作用,药物代谢酶的时间依赖性和混合抑制/诱导
(DME)和转运蛋白,以及基于代谢物的抑制/诱导。由于DDI无法预防,
根据DDI风险指导药物调整的全面药物药代动力学(PK)数据,
需要在药物开发期间进行精心计划的临床前和临床DDI研究。然而,目前在
体外临床前肝脏PK模型,包括微生理系统(MPS),遭受重要的功能性损伤。
局限性,如胎儿表型的表达,药物代谢酶的低表达水平,
转运蛋白,和快速表型去分化(即,短期培养体系)。这项拟议中的技术
特别适用于具有复杂DDI倾向的药物,包括DME的时间依赖性诱导,
运输机
Javelin的总体战略是开发针对药物代谢优化的微生理系统(MPS)
和药代动力学(DMPK)研究,包括与我们的定量系统联合使用的DDI
药理学(QSP)模型,以生成更多的预测性临床前药物数据。SBIR第一阶段项目将
建立最佳的细胞和亲肝因子微环境,以驱动长期的,生理上的-
肝DME和转运蛋白的相关表达和活性。内源性肝细胞因子将是
选择它们的能力,以维持肝细胞的健康和驱动转录因子信号网络,
调节DME和转运蛋白基因的表达。将使用高-
通过量部分因子分析方法并在Javelin的聚碳酸酯中优化(即,无PDM,
最大限度地减少非特异性药物吸附),毫流体,再循环MPS设计用于DMPK研究。所得
培养基补充剂,“DMPK-最佳”将是第一个化学定义的,不含异种蛋白的补充剂,
以驱动持续的DME和转运蛋白基因表达和活性,用于DMPK-DDI研究。标枪的DMPK-
DDI平台将作为低成本的商业可用产品提供给制药公司
有兴趣生成全面、准确、基于人的PK数据,以更好地为其药物开发提供信息
首次人体试验(FIH)的过程和设计。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Murat Cirit', 18)}}的其他基金
Multi-Tissue MAFLD Chip for Mechanism-Based Drug Testing
用于基于机制的药物测试的多组织 MAFLD 芯片
- 批准号:
10484325 - 财政年份:2022
- 资助金额:
$ 25.96万 - 项目类别:
Translational Center of Tissue Chip Technologies for quantitative characterization of Microphysiological Systems
用于微生理系统定量表征的组织芯片技术转化中心
- 批准号:
9275102 - 财政年份:2016
- 资助金额:
$ 25.96万 - 项目类别:
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