Ivermectin Neurotoxicity and ABCB1 Gene Mutations

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

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.

Study Overview

• Status: Completed
• Conditions: DNA Sequencing

• Study Type: Observational
• Enrollment (Actual): 3

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34295
    • UH Montpellier

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Child followed in the pediatric ward of Toulouse University Hospital for the episode of neurotoxicity and his parents

Description

Inclusion Criteria:

• episode of neurotoxicity

Exclusion Criteria:

• NA

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
cerebral spinal fluid dosages	Cerebrospinal fluid test	1 day

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Collaborators: University Hospital, Toulouse; INRAE, Toulouse France; Université Paris-Saclay, Gif-sur-Yvette, France; University Hospital, Montpellier France
• Investigators: Principal Investigator: Séverine CUNAT, PharmD, PhD, University Hospital, Montpellier

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2017
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 30, 2019

Study Registration Dates

• First Submitted: May 16, 2019
• First Submitted That Met QC Criteria: November 20, 2019
• First Posted (Actual): November 22, 2019

Study Record Updates

• Last Update Posted (Actual): September 2, 2020
• Last Update Submitted That Met QC Criteria: September 1, 2020
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: neurotoxicity; ivermectin; ATP binding cassette subfamily B member 1; ABCB1/P-glycoprotein (P-gp); multidrug transporter; drug adverse event; Ivermectin toxicity
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Nervous System Diseases; Poisoning; Neurotoxicity Syndromes
• Other Study ID Numbers: RECHMPL19_0176

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: NC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No