Midazolam Whole Body Physiologically Based Pharmacokinetic Model

Study Overview
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Brief Summary
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This study investigates what independent variables may influence Midazolam Pharmacokinetics in critically ill patients.

Detailed Description
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This study has three specific aims: to create a Midazolam PBPK model based on anthropometric and physiopathological data from enrolled patients; to estimate cerebral and systemic Midazolam concentrations; to assess independent variables about Midazolam pharmacokinetic in critically ill patients.

Official Title
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Whole Body Physiologically Based Pharmacokinetic (PBPK) Model to Estimate Cerebral and Systemic Midazolam Concentrations in ICU Patients Under Sedation.

Conditions
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Respiratory Failure, Coma

Intervention / Treatment
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* Procedure: Blood and urine sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ICU admittance Caucasian Clinical indication of least 72h of continuous sedation with Midazolam MAP between 60 - 150 mmHg, even if obtained with amine support informed consent obtained Exclusion Criteria: Any endocranial lesion, spontaneous or induced PaCO2 > 60 mmHg or < 30 mmHg PaO2 < 50 mmHg Pregnancy Anuria Any transplantation Severe hepatic failure (Child C) Life expectancy < 72h Ketoconazole and antiretrovirals in therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Midazolam<br>Patients will be enrolled within 24h from the beginning of continuous Midazolam perfusion. Blood and urine sampling will follow this schedule: 24h: blood (3ml) 48h: blood (3ml) and urine End of infusion: blood (3ml) 6h after end of infusion: blood (3ml) and urine. Blood samples will be centrifuged for 10 minutes at 3300rpm, then supernatant will be placed into test tubes and stored at -20°C; urine samples will be freeze at -20°C as well. Then all frozen samples will be analyzed to get Midazolam concentrations. | Procedure: Blood and urine sampling<br>* Blood and urine sampling will follow this schedule: 24h: blood (3ml) 48h: blood (3ml) and urine End of infusion: blood (3ml) 6h after end of infusion: blood (3ml) and urine. Blood samples will be centrifuged for 10 minutes at 3300rpm, then supernatant will be placed into test tubes and stored at -20°C; urine samples will be freeze at -20°C as well. Then all frozen samples will be analyzed to get Midazolam concentrations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Midazolam concentration in serum and urine | We will calculate Midazolam AUC in serum and urine using blood and urine samples. With this data we will evaluate the elimination constants and create a Physiologically Based Pharmacokinetic Model for Midazolam simulating the drug concentration profile in brain and fat tissue. The blood and urine samples timing is: 1 blood sample will be gathered after 24h at the beginning of continuous intravenous infusion of Midazolam 1 blood sample and 1 urine sample will be gathered after 48h at the beginning of continuous intravenous infusion of Midazolam 1 blood sample will be gathered at the end of continuous intravenous infusion of Midazolam (the duration of infusion is different for each patient according with clinical case) 1 blood sample and 1 urine sample will be gathered after 6h at the end of continuous intravenous infusion of Midazolam (the duration of infusion is different for each patient according with clinical case) | Participants will be followed for the duration of hospital stay, an expected average of 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fat mass analysis and its importance in drug distribution. | At enrollment we will collect data about fat mass in our population. Our goal is to determine how much this variable can modify the distribution of Midazolam in the body. Statistical analysis will performed to found if different body mass values are correlated with different blood concentration of Midazolam at steady level. | At enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, PBPK, Midazolam, Critically ill patients