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Pharmacokinetics of Amiodarone in Children (PK-AMIO)

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ClinicalTrials.gov Identifier: NCT03842020
Recruitment Status : Recruiting
First Posted : February 15, 2019
Last Update Posted : March 19, 2019
Sponsor:
Collaborator:
URC-CIC Paris Descartes Necker Cochin
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

PK-AMIO study is a population pharmacokinetic study of Amiodarone in children in order to :

  • study the pharmacokinetic parameters (Pop PK) of Amiodarone in children;
  • identify covariates explaining the variability of these pharmacokinetic parameters;
  • study the relationship between the concentration, the efficacy of treatment and its tolerance to optimize the use of Amiodarone in pediatrics.

Indeed, there is no consensus on the optimal oral dosage in children. Few pharmacokinetic studies have been performed with only a small number of patients per study. Our study will include 70 children aged 0 to 18 years old.


Condition or disease Intervention/treatment Phase
Heart Rhythm Disorder Other: Blood pharmacokinetic samples Not Applicable

Detailed Description:

The incidence of supraventricular rhythm disorders in children is 1/250 to 1/1000. Amiodarone is used until the age of 1 year to limit the risk of recurrence. Efficiency is around 60% with no predictive factors identified. According to the study by Dallefeld (2018), unexplained inter-individual variability in pharmacokinetic parameters is 200%. Its adverse effects are numerous and affect 10% of patients. The concentration-effect relationship is poorly known. Amiodarone can cause hypotension and bradycardia. Liver and thyroid function should be monitored as well. Amiodarone is metabolised by cytochromes, mainly CYP3A4. Drug interactions and cytochrome variation in the neonatal period may alter its elimination kinetics. Pharmacokinetic studies have been conducted in adults with target concentrations of 0.5 to 2.5 mg/l.

The efficacy of oral amiodarone in children has been shown in studies in 1980; however, there is no consensus on optimal dosage. Despite its widespread use in children, few pharmacokinetic studies have been conducted in a small number of patients at different doses. The population pharmacokinetics and pharmacodynamics of Amiodarone in children, as well as its general and scientific interest, will be studied in this study. The lack of efficacy and the occurrence of adverse events of Amiodarone in children may be related to the large inter-individual pharmacokinetic variability.

Currently, more than 200 children treated with Amiodarone are being followed at Necker-Enfants malades Hospital.

This prospective study will be conducted in three paediatric services of Necker-Enfants malades Hospital in Paris, France.

Patient selection will take place in the 3 paediatric services. The senior physician proposes the study to holders of parental authority whose child receives or will receive the treatment during its follow-up or hospitalization.

After verification of the inclusion and exclusion criteria, the consent of the parents or parental authority and the child, according to his age, will be obtained.

After agreement, and/or signature of the parents and the non-oral opposition of the child in age to understand the information, the child is sampled according to the following scheme:

  • The samples taken during the introduction of the treatment in hospital will be made to observe the pharmacokinetics at the first dose: 3 samples will be taken in the following time windows: [H0-H3]; [H5-H9] and just before the next dose administration (H24).
  • During the maintenance treatment, a sample will be taken during a scheduled consultation or during a hospitalization.
  • Blood PK samples will be drawn until 1 month after end of treatment.

All patients' samples will be kept for to be analyzed at the Pharmacology department of the Cochin hospital.

No intervention or no charge will be made for this study.

This population pharmacokinetic study in children aims to analyze the concentration-effectiveness and concentration-tolerance relationship to optimize its use.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Population Pharmacokinetics and Pharmacodynamics of Amiodarone in Children": PK-AMIO
Actual Study Start Date : February 13, 2019
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : January 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Amiodarone dosage
Blood pharmacokinetics samples
Other: Blood pharmacokinetic samples
1 or 3 sample(s) will be taken in the following time windows: [H0-H3]; [H5-H9] and just before the next set [H24], depending if the child is or is not admitted to hospital
Other Name: Amiodarone dosage




Primary Outcome Measures :
  1. Maximal Concentration (Cmax) of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  2. Area under the plasma concentration versus time curve (AUC) of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  3. Clearance of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  4. Volume of distribution of amiodarone [ Time Frame: Hour 0 to Hour 24 ]
  5. Half time of amiodarone [ Time Frame: Hour 0 to Hour 24 ]

Secondary Outcome Measures :
  1. Rhythm disorder [ Time Frame: Day 0 ]
    to assess Efficacity - Detection of the rhythm disorder on an ECG or scope (during hospitalization or consultation), or an ECG holter: absence of rhythm disorders at the atrial, junctional or ventricular level Or oral report from parents of rhythm disorder between 2 consultations (palpitation, heart rate acceleration)

  2. Altered liver function [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : gammaglutamyl transferase (GGT) U/L , Alkaline Phosphatase (ALP) U/L, Alanine Transaminase (ALT) U/L Aspartate Transaminase (AST) U/L,Total / conjugated/ free bilirubin µmol/L

  3. Thyroid Dysfunction [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - from blood tests or clinical follow-up : (TSH µmol/l, Free Tri-iodothyronine (FT3) and Free Thyroxine (FT4) pmol/L)

  4. QT and corrected QT duration [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance - QT and corrected QT duration in milliseconds with an ECG

  5. Blood pressure : (PAS)/(PAD) (mmHg) [ Time Frame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months ]
    to assess Tolerance



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All children from 0 to 18 years old treated with Amiodarone for any rhythm disorder, and followed to Necker-Enfants maladies hospital.

Exclusion Criteria:

  • Absence of parental and / or child consent
  • Known liver dysfunction

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): NCT03842020


Contacts
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Contact: Jean-Marc TRELUYER, MD, PhD +33 (0)1 58 41 34 81 jean-marc.treluyer@aphp.fr
Contact: Prissile BAKOUBOULA, PhD +33 (0)1 71 19 64 94 prissile.bakouboula@aphp.fr

Locations
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France
Necker Hospital Recruiting
Paris, France, 75015
Contact: Amelia LEHNERT, MD    +33 (0)6 37 40 74 43    amelialehnert21@yahoo.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Investigators
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Study Director: Jean-Marc TRELUYER, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Damien BONNET, MD, PhD Assistance Publique - Hôpitaux de Paris
Study Director: Sylvain RENOLLEAU, MD, PhD Assistance Publique - Hôpitaux de Paris
Principal Investigator: Amelia LEHNERT, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications:
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03842020     History of Changes
Other Study ID Numbers: APHP180299
2018-A02327-48 ( Registry Identifier: ID-RCB )
First Posted: February 15, 2019    Key Record Dates
Last Update Posted: March 19, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
heart rhythm disorder
Amiodarone
Cardiac arrhythmias
Pediatric
Population pharmacokinetic (Pop PK)
Modeling
Additional relevant MeSH terms:
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Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Amiodarone
Anti-Arrhythmia Agents
Vasodilator Agents
Potassium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Sodium Channel Blockers
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP3A Inhibitors