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Midazolam Whole Body Physiologically Based Pharmacokinetic Model (MidPBPK)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01973894
First Posted: November 1, 2013
Last Update Posted: May 25, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
University of Milan
Information provided by (Responsible Party):
Paolo Severgnini, Università degli Studi dell'Insubria
  Purpose
This study investigates what independent variables may influence Midazolam Pharmacokinetics in critically ill patients.

Condition Intervention
Respiratory Failure Coma Procedure: Blood and urine sampling

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Whole Body Physiologically Based Pharmacokinetic (PBPK) Model to Estimate Cerebral and Systemic Midazolam Concentrations in ICU Patients Under Sedation.

Resource links provided by NLM:


Further study details as provided by Paolo Severgnini, Università degli Studi dell'Insubria:

Primary Outcome Measures:
  • Midazolam concentration in serum and urine [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks ]

    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)


Secondary Outcome Measures:
  • Fat mass analysis and its importance in drug distribution. [ Time Frame: At enrollment ]
    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.


Biospecimen Retention:   Samples Without DNA
serum and urine

Enrollment: 20
Study Start Date: January 2013
Study Completion Date: May 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Midazolam

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

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.


Detailed Description:

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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Critically ill patients in Intensive Care Unit, mechanically ventilated, sedated with midazolam, intravenous continued perfusion.
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01973894


Locations
Italy
Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi
Varese, Italy, 21100
Sponsors and Collaborators
Università degli Studi dell'Insubria
University of Milan
Investigators
Principal Investigator: Paolo Severgnini, Prof. Università degli Studi dell'Insubria, Varese, Italy
  More Information

Responsible Party: Paolo Severgnini, Prof., Università degli Studi dell'Insubria
ClinicalTrials.gov Identifier: NCT01973894     History of Changes
Other Study ID Numbers: 724
First Submitted: August 19, 2012
First Posted: November 1, 2013
Last Update Posted: May 25, 2017
Last Verified: May 2017

Keywords provided by Paolo Severgnini, Università degli Studi dell'Insubria:
PBPK
Midazolam
Pharmacokinetics
Critically ill patients

Additional relevant MeSH terms:
Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action