A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems

Study Overview
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Brief Summary
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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
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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 Potential drugs can be withdrawn from development at any stage of the process if there are concerns over safety.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 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.

Official Title
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A Study of the Pharmacokinetic and Pharmacodynamic Responses in Healthy and Altered Human Cardiovascular Systems

Conditions
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Drug-Related Side Effects and Adverse Reactions, Cardiovascular System Disease

Intervention / Treatment
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* Drug: Albuterol Sulfate
* Drug: Nicardipine Hydrochloride
* Drug: Dobutamine Hydrochloride
* Drug: Phenylephrine Hydrochloride
* Drug: Verapamil Hydrochloride
* Drug: Phentolamine Mesylate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Part A Inclusion Criteria To be included in the study the patient must: Have given written informed consent to participate Male Be aged between 18 and 30 years at the time of first study appointment BMI <30 Deemed healthy to partake in the study at the discretion of the investigator Exclusion Criteria The presence of any of the following will preclude patient inclusion: Less than 18 years old, >30 years old BMI >30 On regular medications Known allergy to medications History of psychiatric, chronic cardiac / respiratory / renal disease Known diagnosis of diabetes Habitual smoker Screening heart rate of less than 60 beats per minute Screening heart rate of greater than 100 beats per minute Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study Current participation in another interventional research study Part B Inclusion Criteria To be included in the study the patient must: Have given written informed consent to participate Male Be aged over 18 years at the time of first study appointment Possess one of the following - known diagnosis of diabetes, known diagnosis of hypertension, obesity (BMI>30), aged >65 Deemed healthy to partake in the study at the discretion of the investigator Exclusion Criteria The presence of any of the following will preclude patient inclusion: Less than 18 years old On regular medications that are contraindicated for co-use with the study drugs Known allergy to medications Screening heart rate of less than 60 beats per minute Screening heart rate of greater than 100 beats per minute Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study Current participation in another interventional research study Part C Inclusion Criteria To be included in the study the patient must: Have given written informed consent to participate Male Be aged over 18 years at the time of first study appointment Clinical diagnosis of autonomic dysfunction BMI<30 Deemed healthy to partake in the study at the discretion of the investigator Exclusion Criteria The presence of any of the following will preclude patient inclusion: Less than 18 years old BMI >30 On regular medication Known allergy to medications History of psychiatric, chronic cardiac / respiratory / renal disease Habitual smoker Screening heart rate of less than 60 beats per minute Screening heart rate of greater than 100 beats per minute Screening blood pressure of less than 100mmHg systolic and/or 55mmHg diastolic Any concomitant condition or circumstance that, at the discretion of the investigator, may affect the participant's ability to complete the study Current participation in another interventional research study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A (Placebo, Salbutamol, Nicardipine, Dobutamine)<br>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) | Drug: Albuterol Sulfate<br>* see arm/group descriptions<br>* Other names: Salbutamol Sulfate;Drug: Nicardipine Hydrochloride<br>* see arm/group descriptions<br>Drug: Dobutamine Hydrochloride<br>* see arm/group descriptions<br>Drug: Placebo<br>* see arm/group descriptions<br>* Other names: 0.9% Sodium Chloride;|
| Experimental: Group B (Placebo, Phenylephrine, Verapamil, Phentolamine)<br>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) | Drug: Phenylephrine Hydrochloride<br>* see arm/group descriptions<br>Drug: Verapamil Hydrochloride<br>* see arm/group descriptions<br>* Other names: Securon IV;Drug: Phentolamine Mesylate<br>* see arm/group descriptions<br>* Other names: Phentolamine Mesilate;Drug: Placebo<br>* see arm/group descriptions<br>* Other names: 0.9% Sodium Chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate | Change in heart rate from baseline over time after administration of drug | At every study visit (each lasting up to 8 hours) | 
| Peripheral blood pressure | Change in resting peripheral blood pressure (systolic, diastolic, pulse pressure and mean pressure) over time after administration of drug | At every study visit (each lasting up to 8 hours) | 
| Central blood pressure | Change in resting central aortic pressure (systolic, diastolic, pulse pressure and mean pressure) from baseline over time after administration of drug | At every study visit (each lasting up to 8 hours) | 
| Cardiac output | Change in cardiac output from baseline over time after administration of drug | At every study visit (each lasting up to 8 hours) | 
| Stroke volume | Change in stroke volume from baseline over time after administration of drug | At every study visit (each lasting up to 8 hours) | 
| ECG/Cardiac monitor | Change in ECG (PR interval/QRS interval/QT interval/QTc interval/RR interval) over time after administration of drug | At every study visit (each lasting up to 8 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma drug concentration (all drugs) | Measure of drug levels (parent compound and active metabolites) at the specified time points | 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) | 
| Plasma drug (active) metabolite concentration (varapamil only) | Measure of drug levels (parent compound and active metabolites) at the specified time points | 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 | Changes in renal function throughout study | Through study completion, up to 4 months | 
| Liver function | Changes in liver function throughout study | Through study completion, up to 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Pharmacodynamics, Adverse reactions, Cardiovascular, Translation, Modelling