Ivermectin Neurotoxicity and ABCB1 Gene Mutations

Study Overview
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Brief Summary
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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.

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

Conditions
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DNA Sequencing

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: episode of neurotoxicity Exclusion Criteria: NA

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 45 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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What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ivermectin, neurotoxicity, ATP binding cassette subfamily B member 1, ABCB1/P-glycoprotein (P-gp), multidrug transporter, drug adverse event, Ivermectin toxicity