Midazolam Whole Body Physiologically Based Pharmacokinetic Model (MidPBPK)

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by Università degli Studi dell'Insubria
Sponsor:
Collaborator:
University of Milan
Information provided by (Responsible Party):
Paolo Severgnini, Università degli Studi dell'Insubria
ClinicalTrials.gov Identifier:
NCT01973894
First received: August 19, 2012
Last updated: October 25, 2013
Last verified: October 2013
  Purpose

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


Condition Intervention Phase
Respiratory Failure
Coma
Procedure: Blood and urine sampling
Phase 4

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 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 ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: Yes ]
    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


Estimated Enrollment: 20
Study Start Date: January 2013
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: November 2013 (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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01973894

Contacts
Contact: Paolo Severgnini, Prof. 0039.0332.278801 paolo.severgnini@uninsubria.it
Contact: Giscardo F. Panzavolta, DM, PhD

Locations
Italy
Azienda Ospedaliera Ospedale di Circolo e Fondazione Macchi Recruiting
Varese, Italy, 21100
Contact: Paolo Severgnini, Prof.    0039.0332.278801    paolo.severgnini@uninsubria.it   
Principal Investigator: Francesco Scaglione, Prof.         
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

No publications provided

Responsible Party: Paolo Severgnini, Prof., Università degli Studi dell'Insubria
ClinicalTrials.gov Identifier: NCT01973894     History of Changes
Other Study ID Numbers: 724
Study First Received: August 19, 2012
Last Updated: October 25, 2013
Health Authority: Italy: National Institute of Health

Keywords provided by 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
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
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

ClinicalTrials.gov processed this record on August 26, 2014