Quantifying the Perturbation of Gadoxetate Kinetics by Metformin and Ciclosporin With Functional Magnetic Resonance Imaging of the Liver
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- To evaluate the rate of gadoxetate uptake
研究概览
简要总结
Identifying drugs at risk of interacting with other drugs, called drug-drug interaction (DDI), early in their development is crucial in avoiding late-stage drug development failures. The liver plays a key role in DDIs , with liver cells playing a major part in the taking up and getting rid of drugs. Currently, there is a lack of safe, widely available tools for testing DDIs in humans, particularly interactions involving liver cell transporters.
This study is part of five work packages under the TRISTAN project (Translational Imaging in Drug Safety Assessment) which aims to improve drug safety using imaging. A pilot study provided proof-of-principle that the imaging procedure, dynamic gadoxetate (a type of dye) enhanced magnetic resonance imaging (DGE-MRI), can be used to measure the effect drugs have on the liver cell transporters in humans, using Rifampicin as a test drug. This study aims to further confirm DGE-MRI as a liver imaging biomarker in humans using two different drugs known to act on these transporters.
All study procedures will be done at Sheffield Teaching Hospitals NHS Foundation Trust at the Royal Hallamshire Hospital. This is the site for University of Sheffield MRI related research. Healthy volunteer participants over the age of 18 years old will be eligible with the aim to recruit 12 volunteers. Each participant will attend 3 visits undertaken in a stepwise manner. Visit A will be for screening, consent and baseline blood tests. Visit B will include two MRI scans with gadoxetate administered at each and blood tests measuring liver function taken prior to each scan. Participants will proceed to Visit C if satisfactory images are obtained during the previous visit. Visit C will mirror Visit B, however either Metformin of Ciclosporin will be administered prior to the first scan. The study duration is three months.
详细描述
The identification of drugs at risk of drug-drug interactions (DDI) early in the drug development life cycle is key to avoid late stage drug development failures. A critical gap in current methodologies is for tools that are widely available and safe to use in humans, and specifically can distinguish between perturbation of hepatocellular uptake, excretion or both.
Dynamic gadoxetate enhanced magnetic resonance imaging (DGE-MRI) is a technique that can potentially fill this gap. The MRI contrast agent gadoxetate is used in clinical routine, it is known to be taken up in hepatocytes by transporters OATPB1 and excreted to bile by MRP2 transporters, and the respective uptake and excretion rates can be quantified with DGE-MRI using suitable MRI scans and data modelling.
Studies in animal models using DGE-MRI on 6 different drugs have clearly demonstrated various levels of drug-induced inhibition of gadoxetate uptake and excretion. Recently, a proof-of-concept study in healthy human volunteers using DGE-MRI to characterise a single drug (rifampicin) has shown a systematic 95% reduction in gadoxetate uptake and 40% reduction in excretion.
Aims
Study objectives The purpose of the current study is to expand on these previous results and use DGE-MRI to measure the inhibition of gadoxetate uptake and excretion in volunteers with two other test drugs, metformin and ciclosporin (Neoral). These drugs are selected because they are commonly used in clinical practice, have a good safety profile and are known to inhibit OATP1B1 and MRP2 function. They should therefore also produce a measurable effect on gadoxetate uptake and excretion rates. If we can show that this is indeed measurable, the results will add further evidence that these effects can be detected by DGE-MRI, improve our understanding of relevant effect size and limits of detection, and help us identify thresholds above which reduction in gadoxetate uptake or excretion would be of concern.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Able to provide informed consent
- •Age above 18 years
- •Able to attend for all scheduled visits
- •Able to adhere to instructions on pre-scan food and drinks intake
- •Able to lie flat for the duration of the scan
排除标准
- •Standard MRI exclusions, including:
- •No history of liver or kidney disease
- •No history of heart failure
- •No history of uncontrolled hypertension
- •No history of malignancy or premalignant conditions, past or present
- •No current uncontrolled infections
- •Not currently pregnant
- •Not currently breastfeeding
- •No regular prescribed medication, except the oral contraceptive pill
- •Cochlear implant
- •Aneurysm clips
- •Neurological stimulator
- •Implanted cardiac devices (ICD, PPM, loop recorders, or any others)
- •Metal heart valve
- •History of retained metal foreign bodies
- •Other implanted metal device which prevents MR imaging
- •Claustrophobia
- •Weight exceeding 140 kg
- •History or allergic reaction to MRI contrast agent
结局指标
主要结局
To evaluate the rate of gadoxetate uptake
时间窗: Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B
quantitative variables extracted from the MRI data. 95% CI on the mean effect size of uptake rate khe (mL/min/100mL)
To evaluate the rate of gadoxetate excretion
时间窗: Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B
quantitative variables extracted from the MRI data. 95% CI on the mean effect size of excretion rate kbh (mL/min/100mL
次要结局
- Evaluate effect size of gadoxetate uptake rates as measured by DGE-MRI in response to test drug administration.(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Evaluate effect size of gadoxetate clearance rates as measured by DGE-MRI in response to test drug administration.(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Evaluate liver function test results in response to test drug administration.(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Evaluate effect size of the drug on relative enhancement ratio of the liver(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Evaluate effect size of the drug on area under the curve in blood concentrations.(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Evaluate the effect size of the drug on liver concentrations.(Visit B which is performed at baseline, Visit C which is performed within 56 days of baseline visit B)
- Diurnal variations in uptake rates in the absence of an intervention(Visit B which is performed at baseline)
- Diurnal variations in excretion rates in the absence of an intervention(Visit B which is performed at baseline)