Article

Pharmacogenomic variability can contribute to differences in
pharmacokinetics and clinical responses. Pediatric patients with cerebral palsy
with genetic variations have not been studied for these potential differences.
OBJECTIVE: To determine the genetic sources of variation in oral baclofen
clearance and clinical responses.
DESIGN: Pharmacogenomic add-on study to
determine variability in oral baclofen clearance and clinical responses. SETTING:
Multicenter study based in academic pediatric cerebral palsy clinics.
PARTICIPANTS: A total of 49 patients with cerebral palsy who had participated in
an oral baclofen pharmacokinetic/pharmacodynamic study. METHODS OR INTERVENTIONS:
Of 53 participants in a pharmacokinetic/pharmacodynamic trial, 49 underwent
genetic analysis of 307 key genes and 4535 single-nucleotide polymorphisms
involved in drug absorption, distribution, metabolism, and excretion.
Associations between genotypes and phenotypes of baclofen disposition
(weight-corrected and allometrically scaled clearance) and clinical endpoints
(improvement from baseline in mean hamstring Modified Tardieu Scale scores from
baseline for improvement of R1 spastic catch) were determined by univariate
analysis with correction for multiple testing by false discovery rate. MAIN
OUTCOME MEASUREMENTS: Primary outcome measures were the genotypic and phenotypic
variability of oral baclofen in allometrically scaled clearance and change in the
Modified Tardieu Scale angle compared to baseline. RESULTS: After univariate
analysis of the data, the SNP of ABCC9 (rs11046232, heterozygous AT versus the
reference TT genotype) was associated with a 2-fold increase in oral baclofen
clearance (mean 0.51 +/- standard deviation 0.05 L/h/kg for the AT genotype
versus 0.25 +/- 0.07 L/h/kg for the TT genotype, adjusted P < .001). Clinical
responses were associated with decreased spasticity by Modified Tardieu Scale in
allelic variants with SNPs ABCC12, SLC28A1, and PPARD. CONCLUSIONS: Genetic
variation in ABCC9 affecting oral baclofen clearance highlights the need for
continued studies of genetic polymorphisms to better characterize variable drug
response in children with cerebral palsy. Single-nucleotide polymorphisms in
ABCC12, SLC28A1, and PPARD were associated with varied responses, which warrants
further investigation to determine their effect on spasticity. LEVEL OF EVIDENCE:
II.
CI - Copyright (c) 2018 American Academy of Physical Medicine and Rehabilitation.
Published by Elsevier Inc. All rights reserved.

Langue : ANGLAIS