Validation of a Physiological Based Pharmacokinetic Model by the Study of Paracetamol Distribution in the Brain Compartments in Brain Injured Patients

February 15, 2019 updated by: Poitiers University Hospital

Brain is composed of several anatomical compartments separated by physiological barriers allowing the maintenance of homeostasis. Furthermore, brain-barriers restrain the diffusion of some drugs in cerebro spinal fluid (CSF) and in extracellular fluid (ECF) of brain tissue, making the development and optimization of dosing regimen of new drugs difficult. Most dosing regimen are determined from the plasma concentration because target site concentrations are difficult to obtain in the brain, hence making the prediction of the therapeutic effect, the adverse effect and the toxicity of a brain- diffused drug difficult. Although quantitative and qualitative differences exist in the processes governing pharmacokinetic (PK) in CSF and brain tissue, CSF is considered as the best surrogate of drugs penetration in the human brain.

A study previously published has evaluated in rats the cerebral distribution of paracetamol, used as a marker of passive diffusion in the ECF by microdialysis in the striatum and in the CSF by microdialysis in the ventricular lateralis and the cistern magna. Authors chose paracetamol, as it has the property to diffuse passively and rapidly in the central nervous system allowing the exclusive description of the relationship between the different compartments of the brain. This study has first revealed an unexpected important difference between the distribution profiles obtained in ECF and CSF. Based on these results, authors developed a physiologically based PK model (PBPK) to describe their results and thereby offering the possibility to perform interspecies simulations to predict central nervous system (CNS) distribution of paracetamol in human. In this study, authors used this model to perform pharmaceutical extrapolations between species converting data from animal to human by replacing obtained data from clinical past studies describing paracetamol distribution in the CSF and in plasma.

Microdialysis allows determination of free extracellular concentrations of drug in different tissues and also in brain. Our research team, INSERM U1070, has several past experiences with studies involving micro-dialysis to study the distribution of antibiotic in tissue in both animal and human including cerebral tissue in rat and human. Recommendation from the scholar society suggests that brain injured patients should benefit from a multimodal monitoring to optimize their care and brain perfusion. This invasive multimodal monitoring consists of measuring the intracranial pressure, the oxygen tissue-pressure, the estimation of the cerebral blood flow-rate by cranial Doppler as well as the monitoring of cerebral ischemic parameters by microdialysis. We also prevent systemic cerebral aggression among which, hyperthermia, explaining the prescription of paracetamol among a large number of brain injured patients. Furthermore setting up of an external ventricular draining (EVD) to treat an intra cranial hypertension is usually necessary to allow the continuous flow of the excess of CSF in the brain ventricle.

Few studies carried on human has aimed at comparing the distribution of drugs in both the CSF and the brain extracellular fluid though it is established that the brain barriers differ in their permeability as well as the drug's concentrations are different between brain compartments. Thus by mean of monitoring through microdialysis and/or through therapeutic EVD, required by brain-injured patients, we aim in our study to explore the pharmacokinetic of paracetamol in the brain ECF, the CSF and the plasma and to validate in man the PBPK developed in rat.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
17

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Poitiers, France, 86000
        • Chu de Poitiers

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Brain injured patient
  • Age ≥ 18 ans
  • Patient with a brain microdialysis monitoring and/or an external ventricular drainage
  • Patient receiving paracetamol for clinical purpose

Exclusion Criteria:

  • Paracetamol allergy
  • Liver failure

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Paracetamol arm
Administration of 10 mg/ml of paracetamol
Drug: Paracetamol

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Area under the curve of paracetamol in the CSF, ECF and plasma.
Time Frame: 24 months
24 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Area under the curve ratio of plasmatic of paracetamol between 2 administrations
Time Frame: 30 months
30 months
Area under the curve ratio of free cerebral concentration (CSF and ECF) of paracetamol between 2 administrations
Time Frame: 30 months
30 months
Maximum concentration of paracetamol in cerebro spinal fluid
Time Frame: 30 months
30 months
Maximum concentration of paracetamol in extra cellular fluid
Time Frame: 30 months
30 months
Minimum concentration of paracetamol in cerebro spinal fluid
Time Frame: 30 months
30 months
Minimum concentration of paracetamol in extra cellular fluid
Time Frame: 30 months
30 months
Elimination half life of paracetamol in cerebro spinal fluid
Time Frame: 30 months
30 months
Elimination half life of paracetamol in extra cellular fluid
Time Frame: 30 months
30 months
Minimum plasma concentration
Time Frame: 30 months
30 months
Volume of distribution
Time Frame: 30 months
30 months
Clearance of paracetamol
Time Frame: 30 months
30 months
Maximum plasma concentration
Time Frame: 30 months
30 months
Elimination half life of paracetamol
Time Frame: 30 months
30 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Poitiers University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 23, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 22, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 19, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 21, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 18, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 15, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
October 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PB-PK BRAIN

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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