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.

Trial registration: ClinicalTrials.gov NCT00607542.

Figure 1

Demographics of patients included in the clinical response scores when shown as an overall composite score. Pharmacokinetic (PK) analysis and pharmacodynamic (PD) analysis were performed from the same group. Gross Motor Function Classification System (GMFCS) scores ranged from II-V.

Figure 2

(A) Relationship between weight-corrected apparent oral baclofen clearance and age. Subjects with the ABCC9 rs11046232 AT genotypes had the highest values for oral baclofen clearance at their respective ages. (B) Significant effect (P < .0001) of the ABCC9 genotype (rs11046232) on the weight-corrected apparent oral clearance of baclofen (L/h/kg) after false discovery rate adjustment. Boxes represent the 25^th and 75^th percentiles; the solid line within the interquartile range represents the median. Whiskers represent the 10^th and 90^th percentiles. All subjects are presented for the heterozygous AT genotype (open symbols), whereas only subjects with data lying beyond the 10^th and 90^th percentiles are presented for the homozygous TT genotype.

Figure 3

(A) Allometric scaling of apparent oral clearance of baclofen (L/h/kg^0.529) removes age-associated changes in age. (B) A significant relationship (P < .001) between the ABCC9 genotype (rs11046232) and allometrically scaled clearance is present after false discovery rate adjustment. Boxes represent the 25^th and 75^th percentiles; the solid line within the interquartile range represents the median. Whiskers represent the 10^th and 90^th percentiles. All 3 subjects with heterozygous genotypes are presented (open symbols), whereas only subjects with data lying beyond the 10^th and 90^th percentiles are presented for the homozygous genotype.

Figure 4

Genetic associations with clinical response to baclofen as indicated by the improvement in the mean Modified Tardieu Scale angle of spastic catch from the baseline visit to the pharmacokinetic study visit, measured in degrees. Positive values indicate a reduction in spasticity relative to baseline. Boxes represent the 25^th and 75^th percentiles; the solid line within the interquartile range represents the median. Whiskers represent the 10^th and 90^th percentiles. All subjects are presented for heterozygous genotypes (open symbols), whereas only subjects with data lying beyond the 10^th and 90^th percentiles are presented for homozygous genotypes. Data are presented for rs16945874 in ABCC12 (A), rs1542283 in SLC28A1 (B), and rs6906237 in PPARD (C). Statistical comparisons were corrected for false discovery rate.