Ivermectin Neurotoxicity and ABCB1 Gene Mutations

DNA Sequencing Clinical Trial

Official title:

First Description of a Severe Ivermectin Neurotoxicity in a Child Carrying ABCB1 Nonsense Mutations.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04174469
• Other study ID #: RECHMPL19_0176
• Status: Completed
• Start date: October 10, 2017
• Est. completion date: April 30, 2019

Study information

• Verified date: May 2019
• Source: University Hospital, Montpellier
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The study report a unique case of severe intoxication in a child treated with oral ivermectin to prevent scabies infection. The ABCB1 gene sequencing found the child compound heterozygote for two nonsense mutations, one in each gene copy. The child had inherited from each parent one of the alleles. Each mutation generate a predicted truncated protein that likely lead to ABCB1 loss of function, and the undesirable effects observed.

The study report a unique case of severe intoxication in a child treated with oral ivermectin to prevent scabies infection. The ABCB1 gene sequencing found the child compound heterozygote for two nonsense mutations, one in each gene copy. The child had inherited from each parent one of the alleles. Each mutation generate a predicted truncated protein that likely lead to ABCB1 loss of function, and the undesirable effects observed.

While in some animals, nonsense ABCB1 mutations can lead to neurotoxicity of several ABCB1-substrate drugs, in humans, ivermectin was considered to have an especially high margin of safety, and nonsense mutations have never been reported before, nor has the neurotoxicity of ivermectin apparently caused by these two mutations never been reported before.

This discovery is of critical importance for the child, since it dictates that clinicians would need to optimize any ABCB1 substrate-based therapy in the future. More generally, such information must be brought to the attention of clinicians' medics, and in particular infectious disease specialists, pediatricians, and general practitioners.

It points the importance of pharmacovigilance, and the benefit of pharmacogenomic genotyping in well-defined phenotype, still too rarely considered in clinical practice before the implementation of a drug treatment.

This work results from a multidisciplinary approach, combining several areas of expertise in clinical pediatrics, pharmacology, biology, and bioinformatics.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: April 30, 2019
• Est. primary completion date: April 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 45 Years

Eligibility

Inclusion Criteria:

• episode of neurotoxicity

Exclusion Criteria:

• NA

Related Conditions & MeSH terms

• DNA Sequencing
• Neurotoxicity Syndromes

Locations

Country	Name	City	State
France	Uh Montpellier	Montpellier

Sponsors (5)

Lead Sponsor	Collaborator
University Hospital, Montpellier	INRAE, Toulouse France, Université Paris-Saclay, Gif-sur-Yvette, France, University Hospital, Montpellier France, University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patient DNA sequencing	Biological diagnostic: genotyping of ABCB1 (NM_000927.4) by using next generation sequencing (Agilent SureSelectQXT®, Miseq® Illumina). Bio-informatic analysis on JSI medical system GmbH sequence pilot CE v4.3.1 software.; Identified mutations were subsequently checked using Sanger sequencing on 3130XL (Applied Biosystems®). Bio-informatic analysis on SeqScape v2.5 software.	1 day
Secondary	ivermectin dosage	Biological diagnostic: blood test of ivermectin dosage (normal level: 46,6 (± 21,9) ng/mL for a single dose of 12 mg after 4H; and according to pharmacokinetics informations of VIDAL referential).	1 day
Secondary	cerebral spinal fluid dosages	Cerebrospinal fluid test	1 day