Ivermectin Neurotoxicity and ABCB1 Gene Mutations

Completed

• Conditions: DNA Sequencing

• Registration Number: NCT04174469
• Lead Sponsor: University Hospital, Montpellier

Brief 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.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-10-10
• Primary Completion: 2019-04-01
• Study Completion: 2019-04-30
• Status Verified: 2019-05
• Study First Submitted: 2019-05-16
• Study First Submitted QC: 2019-11-20
• Study First Posted: 2019-11-22
• Last Update Submitted: 2020-09-01
• Last Update Posted: 2020-09-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

• episode of neurotoxicity

Exclusion Criteria

• NA

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Patient DNA sequencing	1 day	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.

Secondary Outcome Measures

Name	Time	Method
cerebral spinal fluid dosages	1 day	Cerebrospinal fluid test
ivermectin dosage	1 day	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).

Trial Locations

Locations (1)

Uh Montpellier; 🇫🇷 Montpellier, France