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Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy.

ABSTRACT: Purpose of review:a)Despite its widespread use, oral baclofen requires a critical review of the pharmacology to determine potential precision medicine applications to improve medication administration. Discussing the dose?exposure?response relationship of oral baclofen allows a conceptual framework in which designing clinical trials would become more successful. This paper seeks to examine some of the areas where variability in exposures can exist lead to undesired clinical responses. Recent findings:b)Several factors are at play to implement precision medicine with oral baclofen in the pediatric patient with cerebral palsy. Variations in intestinal absorption, oral baclofen clearance, pharmacogenomic variants, and distribution of this medication into the cerebrospinal fluid cause differences in the amount of baclofen available at the GABA-B receptor site to cause a clinical response. Summary:c)Oral baclofen has significant variability in disposition and clinical response. Research to determine the causes for this variability and controlling for these factors would allow improvement in clinical outcomes.

SUBMITTER: McLaughlin MJ

PROVIDER: S-EPMC6774387 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy.

McLaughlin Matthew J MJ Abdel-Rahman Susan S Leeder J Steven JS

Current physical medicine and rehabilitation reports 20190123 1

<h4>Purpose of review</h4>a)Despite its widespread use, oral baclofen requires a critical review of the pharmacology to determine potential precision medicine applications to improve medication administration. Discussing the dose→exposure→response relationship of oral baclofen allows a conceptual framework in which designing clinical trials would become more successful. This paper seeks to examine some of the areas where variability in exposures can exist lead to undesired clinical responses.<h4 ...[more]

PMID: 31579558

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Project description:BackgroundPharmacogenomic 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.ObjectiveTo determine the genetic sources of variation in oral baclofen clearance and clinical responses.DesignPharmacogenomic add-on study to determine variability in oral baclofen clearance and clinical responses.SettingMulticenter study based in academic pediatric cerebral palsy clinics.ParticipantsA total of 49 patients with cerebral palsy who had participated in an oral baclofen pharmacokinetic/pharmacodynamic study.Methods or interventionsOf 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 measurementsPrimary 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.ResultsAfter 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.ConclusionsGenetic 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 evidenceII.

Project description:Background: Oral-gut inflammation has an impact on overall health, placing subjects at risk to acquire chronic conditions and infections. Due to neuromotor disturbances, and medication intake, cerebral palsy (CP) subjects present intestinal constipation, impacting their quality of life (QOL). We aimed to investigate how oral inflammatory levels predicted gut phenotypes and response to therapy. Methods: A total of 93 subjects aging from 5 to 17 years were included in the study, and assigned into one of the 4 groups: CP with constipation (G1, n = 30), CP without constipation (G2, n = 33), and controls without CP with constipation (G3, n = 07) and without CP and without constipation (G4, n = 23). In addition to characterizing subjects' clinical demographics, medication intake, disease severity levels, salivary cytokine levels [TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10], and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Statistical significance was evaluated by Shapiro-Wilks, Student's T-Test, ANOVA, and ANCOVA analysis. Results: Salivary proinflammatory cytokines were highly correlated with the severe form of gut constipation in G1 (P < 0.001), and out of all cytokines IL-1β levels demonstrated highest correlation with all gut constipation (P < 0.05). A significant relationship was found between the type of medication, in which subjects taking Gamma-Aminobutyric Acid (GABA) and GABA+ (GABA in association with other medication) were more likely to be constipated than the other groups (P < 0.01). Cleary salivary inflammatory levels and gut constipation were correlated, and impacted QOL of CP subjects. G1 presented a lower QOL mean score of CPCHILD (49.0 ± 13.1) compared to G2 (71.5 ± 16.7), when compared to G3 (88.9 ± 7.5), and G4 (95.5 ± 5.0) (P < 0.01). We accounted for gingival bleeding as a cofounder of oral inflammation, and here were no differences among groups regarding gender (P = 0.332) and age (P = 0.292). Conclusions: Collectively, the results suggest that saliva inflammatory levels were linked to gut constipation, and that the clinical impact of medications that controlled gut was reliably monitored via oral cytokine levels, providing reliable and non-invasive information in precision diagnostics.

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Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy.

Publications

Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy.

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