Clinical trial NCT03842020: Pharmacokinetics of Amiodarone in Children
Official title: Population Pharmacokinetics and Pharmacodynamics of Amiodarone in Children": PK-AMIO
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Rhythm Disorder
Keywords: heart rhythm disorder
Amiodarone
Cardiac arrhythmias
Pediatric
Population pharmacokinetic (Pop PK)
Modeling
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: URC-CIC Paris Descartes Necker Cochin
First posted: 2019-02-15
Enrollment: 57
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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.

Eligibility 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

Primary outcomes:
measure: Maximal Concentration (Cmax) of amiodarone
timeFrame: Hour 0 to Hour 24
measure: Area under the plasma concentration versus time curve (AUC) of amiodarone
timeFrame: Hour 0 to Hour 24
measure: Clearance of amiodarone
timeFrame: Hour 0 to Hour 24
measure: Volume of distribution of amiodarone
timeFrame: Hour 0 to Hour 24
measure: Half time of amiodarone
timeFrame: Hour 0 to Hour 24
Secondary outcomes:
measure: Rhythm disorder
timeFrame: Day 0
measure: Altered liver function
timeFrame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months
measure: Thyroid Dysfunction
timeFrame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months
measure: QT and corrected QT duration
timeFrame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months
measure: Blood pressure : (PAS)/(PAD) (mmHg)
timeFrame: At the beginning of Amiodarone treatment until through study completion, an average of 18 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Necker Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Marc TRELUYER, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Damien BONNET, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Sylvain RENOLLEAU, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Amelia LEHNERT, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dallefeld SH, Atz AM, Yogev R, Sullivan JE, Al-Uzri A, Mendley SR, Laughon M, Hornik CP, Melloni C, Harper B, Lewandowski A, Mitchell J, Wu H, Green TP, Cohen-Wolkowiez M. A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data. J Pharmacokinet Pharmacodyn. 2018 Jun;45(3):419-430. doi: 10.1007/s10928-018-9576-y. Epub 2018 Feb 12.
citation: Garson A Jr, Gillette PC, McVey P, Hesslein PS, Porter CJ, Angell LK, Kaldis LC, Hittner HM. Amiodarone treatment of critical arrhythmias in children and young adults. J Am Coll Cardiol. 1984 Oct;4(4):749-55. doi: 10.1016/s0735-1097(84)80402-7.
citation: Coumel P, Fidelle J. Amiodarone in the treatment of cardiac arrhythmias in children: one hundred thirty-five cases. Am Heart J. 1980 Dec;100(6 Pt 2):1063-9. doi: 10.1016/0002-8703(80)90214-8.
citation: Bucknall CA, Keeton BR, Curry PV, Tynan MJ, Sutherland GR, Holt DW. Intravenous and oral amiodarone for arrhythmias in children. Br Heart J. 1986 Sep;56(3):278-84. doi: 10.1136/hrt.56.3.278.
citation: Pollak PT, Bouillon T, Shafer SL. Population pharmacokinetics of long-term oral amiodarone therapy. Clin Pharmacol Ther. 2000 Jun;67(6):642-52. doi: 10.1067/mcp.2000.107047.