Pharmacodynamic Interaction of REMI and DMED

Study Overview
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Brief Summary
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The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth. These changes will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Detailed Description
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This study is designed to investigate whether the use of a combination of dexmedetomidine and remifentanil is clinically useful to provide anesthesia during surgical and diagnostic procedures and whether it could be used for anesthetic induction. Furthermore the aim is to gain better insights in the required dosing regimens, the inter-individual variability in response towards the combination and the associated side effects. Better characterization of this drug-drug interaction will presumably lead to more precise dosing regimens, which in turn, will lead to a reduction in the occurrence of oversedation, side effects and recovery times. The objective is to map the pharmacokinetic / pharmacodynamic interaction between dexmedetomidine and remifentanil by observing changes in anesthetic depth, measured by hypnotic and analgesic endpoints such as modified observer's assessment of alertness and sedation scale (MOAA/S), response to electrical stimuli, response to laryngoscopy and electroencephalogram (EEG) derived indices. These effects will be related to drug concentrations using pharmacokinetic/pharmacodynamic (PKPD) modeling.

Official Title
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Pharmacodynamic Interactions Between Remifentanil and Dexmedetomidine (PIRAD)

Conditions
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Anesthesia

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Remifentanil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists (ASA) Physical Status 1 No medical history of significance No chronic use of medication, drugs, tobacco or more than 20 gr alcohol daily (oral contraceptives excluded). Concerning the cognitive function: Volunteers are considered to have sufficient cognitive reserve if they are able to read and comprehend the patient information form, if they can adequately answer the anamnestic questions during the screening process and if they are allowed to provide legitimate written informed consent. No selection will be made regarding ethnic background No exclusion criterium is present Exclusion Criteria: Known intolerance to dexmedetomidine or remifentanil Volunteer refusal Age < 18 years or >70 years Pregnancy, or currently nursing Hairstyle with dreadlocks (EEG-monitoring will not be possible) Body mass index (BMI) <18 or >30 kg/m2. Neurological disorder (epilepsy, the presence of a brain tumor, a history of brain surgery, hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain trauma, a subarachnoidal bleeding, TIA or cerebral infarct, psychosis or dementia , schizophrenia, alcohol or drug abuse). Diseases involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: Supportive Care
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All volunteers will receive 2 standardized anesthesia sessions with a washout period of at least one week between sessions. During the first session volunteers will receive dexmedetomidine, during the second session they will first receive remifentanil and afterwards the combination of drugs will be administered. Anesthetic depth will be evaluated by MOAA/S scores (see table 2), testing of tolerance to electrical stimuli and laryngoscopy. Furthermore multichannel EEG-data will be collected to get insight in the drug dependent characteristics. Measured effects will be related to drug plasma concentrations.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine only<br>Dexmedetomidine will be administered by effect-site TCI according to the Hannivoort model extended with an effect-site rate constant of 0.0428min-1. A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (40 min), 3 ng/ml (50 min), 4 ng/ml (40 min), 5 ng/ml (40 min) and 8 ng/ml (70 min). | Drug: Dexmedetomidine<br>* Single drug administration<br>* Other names: Dexdor;|
| Experimental: Remifentanil only<br>Remifentanil will be administered by effect-site TCI according to the Eleveld model. A stepwise increasing dosing regimen will be given, with concentrations targeting an effect site concentration of 1 ng/ml (12 min), 2 ng/ml (12 min), 3 ng/ml (12 min), 5 ng/ml (12 min) and 7 ng/ml (12 min). | Drug: Remifentanil<br>* Single drug administration<br>* Other names: Ultiva;|
| Experimental: Dexmedetomidine-Remifentanil interaction<br>A fixed background dose of dexmedetomidine will be given, this will be calculated after the first 5 subjects completed the dexmedetomidine only session. It will be set to 50% of the observed mean EC50TOL (Tolerance of Laryngoscopy). Remifentanil infusion will be administered by effect site TCI with stepwise increasing targets of 0.5 - 1.0 - 1.5 - 2.0 - 2.5 - 3.0 - 4.0 ng/ml, each lasting for 15 minutes. | Drug: Dexmedetomidine<br>* Single drug administration<br>* Other names: Dexdor;Drug: Remifentanil<br>* Single drug administration<br>* Other names: Ultiva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance of Laryngoscopy (TOL) | Tolerance of a laryngoscopy (yes/no) will be tested at the end of each infusion step during both studydays, when MOAA/s is 0 / 1 and will be related to the drug concentration(s). | 35 - 255 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified observer's assessment of alertness and sedation scale (MOAA/s) | An hypnotic endpoint measuring depth of anesthesia. | During anesthesia sessions day 1 and day 2 | 
| Electrical stimulus | Measuring analgesia by observing response to a standardized electrical stimulus | During anesthesia sessions day 1 and day 2 | 
| Electroencephalogram (EEG) | A multichannel electroencephalogram will be recorded | During anesthesia sessions day 1 and day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dexmedetomidine, Remifentanil, Pharmacodynamics, Interaction