A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Heart rate
研究概览
简要总结
Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. This study aims to develop an in silico model of the human cardiovascular system that can be used to predict unwanted cardiovascular effects of drugs. This will be achieved through a drug administration study that will generate comprehensive pharmacokinetic and pharmacodynamic data following the administration of the following drugs, all known to have effects on the cardiovascular system. Half the participants will receive: Placebo, Salbutamol, Nicardipine, Dobutamine and the other half will receive Placebo, Phenylephrine, Verapamil, Phentolamine.
详细描述
Safety is an integral part of developing new medicines. Potential drugs can be withdrawn from development at any stage of the process if there are concerns over safety. In recent years, computer models that recreate physiology have been increasingly adopted in various aspects of drug development, including safety, to predict the effects of new drugs. The accuracy of this predictive model is however, dependent on the ability for animal data (which the model is usually based on) to be 'translated' to human data. As no animal is identical to humans, the difference between species needs to be understood for the model to be accurate.
Unwanted effects on the cardiovascular system is one of the most common causes of safety related discontinuation of a drug. The present study focuses on generating high quality human cardiovascular data that is comparable with existing animal data. This will be achieved through the collection of detailed pharmacokinetic and pharmacodynamic data following administration of drugs that are known to affect the cardiovascular system through a range of mechanisms. This will be first performed in healthy participants before extending it to those with pre-existing (or risk-factors for) cardiovascular disease. The aim is to understand the differences between species and the study populations and using the collected data to help inform how a translational model is to be built.
Study Design: Single centre, single (participant) blind, within subject, drug administration study
Drugs used in study:
- Salbutamol - a beta-2-adrenergic agonist
- Nicardipine - a dihydropyridine calcium channel antagonist
- Dobutamine - a beta-1-adrenergic agonist
- Phenylephrine - a selective alpha-1-adrenergic agonist
- Verapamil - a phenylalkylamine calcium channel antagonist
- Phentolamine - a non-selective alpha adrenergic antagonist
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage infusion with dose increasing at each stage. Each stage will be 30 minutes in duration.
Placebo; Salbutamol(Albuterol) Sulfate (Dose: 2mcg/min, 5mcg/min, 10mcg/min); Nicardipine Hydrochloride (Dose: 1mg/hr, 2.5mg/hr, 5mg/hr); Dobutamine Hydrochloride (Dose: 1mcg/kg/min, 2.5mcg/kg/min, 5mcg/kg/min)
干预措施: Albuterol Sulfate (Drug)
Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage infusion with dose increasing at each stage. Each stage will be 30 minutes in duration.
Placebo; Salbutamol(Albuterol) Sulfate (Dose: 2mcg/min, 5mcg/min, 10mcg/min); Nicardipine Hydrochloride (Dose: 1mg/hr, 2.5mg/hr, 5mg/hr); Dobutamine Hydrochloride (Dose: 1mcg/kg/min, 2.5mcg/kg/min, 5mcg/kg/min)
干预措施: Nicardipine Hydrochloride (Drug)
Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage infusion with dose increasing at each stage. Each stage will be 30 minutes in duration.
Placebo; Salbutamol(Albuterol) Sulfate (Dose: 2mcg/min, 5mcg/min, 10mcg/min); Nicardipine Hydrochloride (Dose: 1mg/hr, 2.5mg/hr, 5mg/hr); Dobutamine Hydrochloride (Dose: 1mcg/kg/min, 2.5mcg/kg/min, 5mcg/kg/min)
干预措施: Dobutamine Hydrochloride (Drug)
Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage infusion with dose increasing at each stage. Each stage will be 30 minutes in duration.
Placebo; Salbutamol(Albuterol) Sulfate (Dose: 2mcg/min, 5mcg/min, 10mcg/min); Nicardipine Hydrochloride (Dose: 1mg/hr, 2.5mg/hr, 5mg/hr); Dobutamine Hydrochloride (Dose: 1mcg/kg/min, 2.5mcg/kg/min, 5mcg/kg/min)
干预措施: Placebo (Drug)
Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage bolus with dose increasing at each stage. Each stage will be 30 minutes apart.
Placebo; Phenylephrine Hydrochloride (Dose: 100mcg, 200mcg, 300mcg); Verapamil Hydrochloride (Dose: 1mg, 2.5mg, 5mg); Phentolamine Mesylate (Dose: 1mg, 2mg, 3mg)
干预措施: Phenylephrine Hydrochloride (Drug)
Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage bolus with dose increasing at each stage. Each stage will be 30 minutes apart.
Placebo; Phenylephrine Hydrochloride (Dose: 100mcg, 200mcg, 300mcg); Verapamil Hydrochloride (Dose: 1mg, 2.5mg, 5mg); Phentolamine Mesylate (Dose: 1mg, 2mg, 3mg)
干预措施: Verapamil Hydrochloride (Drug)
Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage bolus with dose increasing at each stage. Each stage will be 30 minutes apart.
Placebo; Phenylephrine Hydrochloride (Dose: 100mcg, 200mcg, 300mcg); Verapamil Hydrochloride (Dose: 1mg, 2.5mg, 5mg); Phentolamine Mesylate (Dose: 1mg, 2mg, 3mg)
干预措施: Phentolamine Mesylate (Drug)
Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)
Participants will receive each drug, to be given on separate study days. The drugs will be given as a 3 stage bolus with dose increasing at each stage. Each stage will be 30 minutes apart.
Placebo; Phenylephrine Hydrochloride (Dose: 100mcg, 200mcg, 300mcg); Verapamil Hydrochloride (Dose: 1mg, 2.5mg, 5mg); Phentolamine Mesylate (Dose: 1mg, 2mg, 3mg)
干预措施: Placebo (Drug)
结局指标
主要结局
Heart rate
时间窗: At every study visit (each lasting up to 8 hours)
Change in heart rate from baseline over time after administration of drug
Stroke volume
时间窗: At every study visit (each lasting up to 8 hours)
Change in stroke volume from baseline over time after administration of drug
Peripheral blood pressure
时间窗: At every study visit (each lasting up to 8 hours)
Change in resting peripheral blood pressure (systolic, diastolic, pulse pressure and mean pressure) over time after administration of drug
Cardiac output
时间窗: At every study visit (each lasting up to 8 hours)
Change in cardiac output from baseline over time after administration of drug
Central blood pressure
时间窗: At every study visit (each lasting up to 8 hours)
Change in resting central aortic pressure (systolic, diastolic, pulse pressure and mean pressure) from baseline over time after administration of drug
ECG/Cardiac monitor
时间窗: At every study visit (each lasting up to 8 hours)
Change in ECG (PR interval/QRS interval/QT interval/QTc interval/RR interval) over time after administration of drug
次要结局
- Plasma drug (active) metabolite concentration (varapamil only)(Throughout the study, estimated 6 months per part. Taken at specified timepoints (5mins, 10min, 15mins, 30mins, 35mins, 40mins, 45mins, 60mins, 65mins, 70mins, 75mins, 90mins, 120mins, 150mins, 180mins, 240mins, 360mins))
- Renal Function(Through study completion, up to 4 months)
- Plasma drug concentration (all drugs)(These will be measured during each part of the study, estimated 6 months per part. Taken at: -(5mins, 10mins,15mins, 30mins, 35mins, 40mins, 45mins, 60mins, 65mins, 70mins, 75mins, 90mins, 120mins, 150mins, 180mins, 240mins, 360mins))
- Liver function(Through study completion, up to 4 months)
研究者
Joseph Cheriyan, MD
Dr
Cambridge University Hospitals NHS Foundation Trust