Clinical trial NCT04174469: Ivermectin Neurotoxicity and ABCB1 Gene Mutations
Official title: First Description of a Severe Ivermectin Neurotoxicity in a Child Carrying ABCB1 Nonsense Mutations.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: DNA Sequencing
Keywords: ivermectin
neurotoxicity
ATP binding cassette subfamily B member 1
ABCB1/P-glycoprotein (P-gp)
multidrug transporter
drug adverse event
Ivermectin toxicity
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
Collaborators: name: University Hospital, Toulouse
name: INRAE, Toulouse France
name: Université Paris-Saclay, Gif-sur-Yvette, France
name: University Hospital, Montpellier France
First posted: 2019-11-22
Enrollment: 3
Sex: ALL
Minimum age (years): 10
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Child followed in the pediatric ward of Toulouse University Hospital for the episode of neurotoxicity and his parents

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.


Eligibility criteria: Inclusion Criteria:

* episode of neurotoxicity

Exclusion Criteria:

* NA

Primary outcomes:
measure: Patient DNA sequencing
timeFrame: 1 day
Secondary outcomes:
measure: ivermectin dosage
timeFrame: 1 day
measure: cerebral spinal fluid dosages
timeFrame: 1 day
Other outcomes:
Locations:
city: Montpellier
country: France
facility: Uh Montpellier
Study officials:
affiliation: University Hospital, Montpellier
name: Séverine CUNAT, PharmD, PhD
role: PRINCIPAL_INVESTIGATOR
References: