Pharmacokinetics of Amiodarone in Children

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Population Pharmacokinetics and Pharmacodynamics of Amiodarone in Children: PK-AMIO

Conditions
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Heart Rhythm Disorder

Intervention / Treatment
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* Other: Blood pharmacokinetic samples


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amiodarone dosage<br>Blood pharmacokinetics samples | Other: Blood pharmacokinetic samples<br>* 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<br>* Other names: Amiodarone dosage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Concentration (Cmax) of amiodarone |  | Hour 0 to Hour 24 | 
| Area under the plasma concentration versus time curve (AUC) of amiodarone |  | Hour 0 to Hour 24 | 
| Clearance of amiodarone |  | Hour 0 to Hour 24 | 
| Volume of distribution of amiodarone |  | Hour 0 to Hour 24 | 
| Half time of amiodarone |  | Hour 0 to Hour 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rhythm disorder | 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) | Day 0 | 
| Altered liver function | 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 | At the beginning of Amiodarone treatment until through study completion, an average of 18 months | 
| Thyroid Dysfunction | to assess Tolerance - from blood tests or clinical follow-up : (TSH µmol/l, Free Tri-iodothyronine (FT3) and Free Thyroxine (FT4) pmol/L) | At the beginning of Amiodarone treatment until through study completion, an average of 18 months | 
| QT and corrected QT duration | to assess Tolerance - QT and corrected QT duration in milliseconds with an ECG | At the beginning of Amiodarone treatment until through study completion, an average of 18 months | 
| Blood pressure : (PAS)/(PAD) (mmHg) | to assess Tolerance | At the beginning of Amiodarone treatment until through study completion, an average of 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart rhythm disorder, Amiodarone, Cardiac arrhythmias, Pediatric, Population pharmacokinetic (Pop PK), Modeling