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Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.

ABSTRACT: BACKGROUND: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.

SUBMITTER: McLaughlin MJ

PROVIDER: S-EPMC5880219 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.

McLaughlin Matthew J MJ He Yang Y Brunstrom-Hernandez Janice J Thio Liu Lin LL Carleton Bruce C BC Ross Colin J D CJD Gaedigk Andrea A Lewandowski Andrew A Dai Hongying H Jusko William J WJ Leeder J Steven JS

PM & R : the journal of injury, function, and rehabilitation 20170901 3

<h4>Background</h4>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.<h4>Objective</h4>To determine the genetic sources of variation in oral baclofen clearance and clinical responses.<h4>Design</h4>Pharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.<h4>Setting</h4>Multicenter s ...[more]

PMID: 28867665

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Project description:Cerebral palsy is primarily an upper motor neuron disease that results in a spectrum of progressive movement disorders. Secondary to the neurological lesion, muscles from patients with cerebral palsy are often spastic and form debilitating contractures that limit range of motion and joint function. With no genetic component, the pathology of skeletal muscle in cerebral palsy is a response to aberrant neurological input in ways that are not fully understood. This study was designed to gain further understanding of the skeletal muscle response to cerebral palsy using microarrays and correlating the transcriptional data with functional measures. Hamstring biopsies from gracilis and semitendinosus muscles were obtained from a cohort of patients with cerebral palsy (n=10) and typically developing patients (n=10) undergoing surgery. Affymetrix HG-U133A 2.0 chips (n=40) were used and expression data was verified for 6 transcripts using quantitative real-time PCR, as well as for two genes not on the microarray. Chips were clustered based on their expression and those from patients with cerebral palsy clustered separately. Significant genes were determined conservatively based on the overlap of three summarization algorithms (n=1,398). Significantly altered genes were analyzed for over-representation among gene ontologies, transcription factors, pathways, microRNA and muscle specific networks. These results centered on an increase in extracellular matrix expression in cerebral palsy as well as a decrease in metabolism and ubiquitin ligase activity. The increase in extracellular matrix products was correlated with mechanical measures demonstrating the importance in disability. These data lay a framework for further studies and novel therapies. Skeletal muscle biopsies from both the gracilis and semitendinosus were obtained during surgery for 20 pediatric subjects for affymetrix microarray analysis. We obtained a group of 10 patients undergoing medial hamstring lengthening in the cerebral palsy group and 10 patients undergoing ACL reconstruction with hamstring autograft in the control group. This provided 40 microarrays in 4 groups to analyze the effect of cerebral palsy and also differences between muscles.

Project description:BackgroundDespite being a common procedure, there are no standard protocols for postoperative immobilization and rehabilitation following reconstructive hip surgery in children with cerebral palsy (CP). The purpose of this study was to investigate variability in postoperative management and physical therapy (PT) recommendations among orthopaedic surgeons treating hip displacement in children with CP.MethodsAn invitation to participate in an anonymous, online survey was sent to 44 pediatric orthopaedic surgeons. The case of a child undergoing bilateral femoral varus derotation osteotomies and adductor tenotomies was presented. Surgeons were asked to consider their typical practice and the case scenario when answering questions related to immobilization, weight-bearing, and rehabilitation. Recommendations with increasingly complex surgical interventions and different age or level of motor function were also assessed.ResultsTwenty-eight orthopaedic surgeons from 9 countries with a mean 21.3 years (range: 5 to 40 y) of experience completed the survey. Postoperative immobilization was recommended by 86% (24/28) of respondents with 7 different methods of immobilization identified. All but 1 (23/24) reported immobilizing full time. Most (20/23) reported using immobilization for 4 to 6 weeks. Return to weight-bearing varied from 0 to 6 weeks for partial weight-bearing and 0 to 12 weeks for full weight-bearing. PT in the first 1 to 2 weeks postoperatively was reported as unnecessary by 29% (8/28) of surgeons. PT for range of motion, strengthening, and return to function was recommended by 96% (27/28) of surgeons, starting at a mean of 2.6 weeks postoperatively (range: 0 to 16 wk). Only 48% (13/27) reported all of their patients would receive PT for these goals in their practice setting. Inpatient rehabilitation was available for 75% (21/28) but most surgeons (17/21) reported this was accessed by 20% or fewer of their patients.ConclusionsPostoperative immobilization and PT recommendations were highly variable among surgeons. This variability may influence surgical outcomes and complication rates and should be considered when evaluating procedures. Further study into the impact of postoperative immobilization and rehabilitation is warranted.

Dataset Information

Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.

Publications

Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy.

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