A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems
- Conditions
- Drug-Related Side Effects and Adverse ReactionsCardiovascular System Disease
- Interventions
- Registration Number
- NCT03098680
- Brief Summary
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.
- Detailed Description
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 Potential drugs can be withdrawn from development at any stage of the process if there are concerns over safety.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:
1. Salbutamol - a beta-2-adrenergic agonist
2. Nicardipine - a dihydropyridine calcium channel antagonist
3. Dobutamine - a beta-1-adrenergic agonist
4. Phenylephrine - a selective alpha-1-adrenergic agonist
5. Verapamil - a phenylalkylamine calcium channel antagonist
6. Phentolamine - a non-selective alpha adrenergic antagonist
Study Population:
The study will take place in three parts (A, B and C), with each part representing population groups that are of interest.
Part A (16 participants): Healthy individuals with no identifiable cardiovascular risk factors will be recruited for this part of the study. The aim of this part is to enable the collection of physiological data after drug administration in a 'normal' cardiovascular system.
Part B (8 participants): Part B will involve the recruitment of participants who may possess an altered/challenged cardiovascular system. Participants recruited will possess one of the following factors: known diagnosis of diabetes, known diagnosis of hypertension, obesity (BMI\>30), age \>65. The data collected will provide information on how potential changes to baseline cardiovascular physiology may affect the effect of the drug.
Part C (8 participants): In order to understand the impact of medicines on cardiovascular physiology in the absence of the autonomic nervous system regulation, we will recruit participants with dysfunction of the autonomic system to Part C of the study.
Maximum duration of participation for each participant:
1x screening (1 hour duration), 4x study visits (8 hour duration each) with minimum 72 hours gap in between visits. Maximum duration is 4 months to complete all visits.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Male
- Target Recruitment
- 18
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group A (Placebo, Salbutamol, Nicardipine, Dobutamine) Dobutamine Hydrochloride 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) Group A (Placebo, Salbutamol, Nicardipine, Dobutamine) Albuterol Sulfate 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) Group B (Placebo, Phenylephrine, Verapamil, Phentolamine) Phentolamine Mesylate 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) Group B (Placebo, Phenylephrine, Verapamil, Phentolamine) Placebo 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) Group A (Placebo, Salbutamol, Nicardipine, Dobutamine) Nicardipine Hydrochloride 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) Group A (Placebo, Salbutamol, Nicardipine, Dobutamine) Placebo 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) Group B (Placebo, Phenylephrine, Verapamil, Phentolamine) Phenylephrine Hydrochloride 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) Group B (Placebo, Phenylephrine, Verapamil, Phentolamine) Verapamil Hydrochloride 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)
- Primary Outcome Measures
Name Time Method Heart rate At every study visit (each lasting up to 8 hours) Change in heart rate from baseline over time after administration of drug
Stroke volume 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 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 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 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 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
- Secondary Outcome Measures
Name Time Method 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) Measure of drug levels (parent compound and active metabolites) at the specified time points
Renal Function Through study completion, up to 4 months Changes in renal function throughout study
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) Measure of drug levels (parent compound and active metabolites) at the specified time points
Liver function Through study completion, up to 4 months Changes in liver function throughout study
Trial Locations
- Locations (1)
Addenbrooke's Hospital
🇬🇧Cambridge, Cambridgeshire, United Kingdom