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

Matthew J. McLaughlin, Yang He, Janice Brunstrom-Hernandez, Liu Lin Thio, Bruce C. Carleton, Colin J.D. Ross, Andrea Gaedigk, Andrew Lewandowski, Hongying Dai, William J. Jusko, J. Steven Leeder

Research output: Contribution to journalArticle

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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

Original languageEnglish (US)
Pages (from-to)235-243
Number of pages9
JournalPM and R
Volume10
Issue number3
DOIs
StatePublished - Mar 2018

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Baclofen
Pharmacogenetics
Cerebral Palsy
Single Nucleotide Polymorphism
Pharmacokinetics
Genotype
Pediatrics
Muscle Spasticity
Genetic Association Studies
Genetic Polymorphisms
Pharmaceutical Preparations
Multicenter Studies
Outcome Assessment (Health Care)
Weights and Measures
Genes

ASJC Scopus subject areas

  • Physical Therapy, Sports Therapy and Rehabilitation
  • Rehabilitation
  • Neurology
  • Clinical Neurology

Cite this

McLaughlin, M. J., He, Y., Brunstrom-Hernandez, J., Thio, L. L., Carleton, B. C., Ross, C. J. D., ... Leeder, J. S. (2018). Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. PM and R, 10(3), 235-243. https://doi.org/10.1016/j.pmrj.2017.08.441

Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. / McLaughlin, Matthew J.; He, Yang; Brunstrom-Hernandez, Janice; Thio, Liu Lin; Carleton, Bruce C.; Ross, Colin J.D.; Gaedigk, Andrea; Lewandowski, Andrew; Dai, Hongying; Jusko, William J.; Leeder, J. Steven.

In: PM and R, Vol. 10, No. 3, 03.2018, p. 235-243.

Research output: Contribution to journalArticle

McLaughlin, MJ, He, Y, Brunstrom-Hernandez, J, Thio, LL, Carleton, BC, Ross, CJD, Gaedigk, A, Lewandowski, A, Dai, H, Jusko, WJ & Leeder, JS 2018, 'Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy', PM and R, vol. 10, no. 3, pp. 235-243. https://doi.org/10.1016/j.pmrj.2017.08.441
McLaughlin MJ, He Y, Brunstrom-Hernandez J, Thio LL, Carleton BC, Ross CJD et al. Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. PM and R. 2018 Mar;10(3):235-243. https://doi.org/10.1016/j.pmrj.2017.08.441
McLaughlin, Matthew J. ; He, Yang ; Brunstrom-Hernandez, Janice ; Thio, Liu Lin ; Carleton, Bruce C. ; Ross, Colin J.D. ; Gaedigk, Andrea ; Lewandowski, Andrew ; Dai, Hongying ; Jusko, William J. ; Leeder, J. Steven. / Pharmacogenomic Variability of Oral Baclofen Clearance and Clinical Response in Children With Cerebral Palsy. In: PM and R. 2018 ; Vol. 10, No. 3. pp. 235-243.
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AU - Thio, Liu Lin

AU - Carleton, Bruce C.

AU - Ross, Colin J.D.

AU - Gaedigk, Andrea

AU - Lewandowski, Andrew

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N2 - 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

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