Midazolam Whole Body Physiologically Based Pharmacokinetic Model

N/ACompletedNCT01973894

Università degli Studi dell'Insubria20 enrolled

Overview

This study investigates what independent variables may influence Midazolam Pharmacokinetics in critically ill patients.

This study has three specific aims: 1. to create a Midazolam PBPK model based on anthropometric and physiopathological data from enrolled patients; 2. to estimate cerebral and systemic Midazolam concentrations; 3. to assess independent variables about Midazolam pharmacokinetic in critically ill patients.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Respiratory Failure Coma

Interventions

Blood and urine samplingPROCEDURE

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (1)

Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi

Varese, Italy

Outcomes

Primary Outcomes

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)

Time frame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks

Secondary Outcomes

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.

Time frame: At enrollment

Data from ClinicalTrials.gov

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