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.
Project description: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.
Project description:The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10?min of the final dose of DW or each herbal medication, baclofen (1?mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42-4.10?hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a ) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.
Project description:To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use.Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland).R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children.The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.
Project description:Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60-120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34-2), clearance (Cl/F) 11.6 L/h (10.8-12.3) and volume of distribution (Vd/F) 72.8 L (66.5-80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19-65), 21% (16-27), and 22% (11-36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21-26). No serious adverse event was reported. Registration: EudraCT #2013-003412-46.
Project description:RATIONALE:There is presently no approved single treatment for dual alcohol and nicotine dependencies. OBJECTIVE:This pilot study investigated baclofen effects in alcoholic smokers. METHODS:This was a preliminary double-blind placebo-controlled randomized clinical study with 30 alcoholic smokers randomized to baclofen at 80 mg/day or placebo. A subgroup (n=18) participated in an alcohol cue-reactivity experiment. RESULTS:Baclofen, compared with placebo, significantly decreased the percent days of abstinence from alcohol-tobacco co-use (p=0.004). Alcohol dependence severity moderated baclofen effects, with the higher severity group having the greater baclofen response (p<0.001). Although the percent days of alcohol-tobacco co-use declined in both groups, this decline was greater after placebo than baclofen (p<0.001). Secondary analyses on alcohol or tobacco use alone suggested that the increase in percent days of co-abstinence was driven by the medication differences on heavy drinking days and on percent days smoking. In the cue-reactivity substudy, baclofen slightly decreased alcohol urge (p=0.058) and significantly reduced salivation (p=0.001), but these effects were not related to cue type. CONCLUSIONS:This study provides preliminary evidence suggesting a possible role of baclofen in the treatment of alcoholic smokers. However, the mixed results and the small sample require larger confirmatory studies.
Project description:Baclofen is a promising treatment for alcohol use disorders (AUD), although its clinical response in humans is mixed. The present study aimed at investigating the impact of baclofen treatment on cue-induced brain activation pattern and its relationship with relapse outcomes.Twenty-three inpatients with AUD underwent a functional magnetic resonance imaging cue-reactivity task before beginning medication with baclofen and 2 weeks later. Twelve additional inpatients with AUD, who did not receive any anticraving medications, formed the control group. All subjects were prospectively followed up for 90 days post-discharge or until lapse to first alcohol use.Whole-brain linear mixed effects analysis revealed a significant group-by-time interaction with greater activation of the bilateral dorsolateral pre-frontal cortex and right anterior cingulate cortex (ACC) following baclofen treatment in comparison with the control group. Further, cox regression analysis revealed that increased activation of ACC and deactivation of insular cortex (IC) was associated with longer time to first alcohol use only in the baclofen treatment group but not in the control group.This study provides preliminary evidence for the neural predictors of baclofen treatment response in AUD. Baclofen treatment in AUD was associated with changes in cue-reactivity at critical brain regions within the incentive-salience network. Importantly, baclofen treatment-related specific activation of regions involved in cognitive control (ACC) and deactivation of regions involved in reward anticipation (IC) prolonged the time to first alcohol drink.
Project description:The extent to which pharmacogenomic-guided medication use has been adopted in various health systems is unclear. To assess the uptake of pharmacogenomic-guided medication use, we determined its frequency across our health system, which does not have a structured testing program. Using a multisite clinical data repository, we identified adult patients' first prescribed medications between January 2011 and December 2013 and investigated the frequency of germline and somatic pharmacogenomic testing, by the Pharmacogenomics Knowledgebase level of the US Food and Drug Administration label information. There were 268,262 medication orders for drugs with germline pharmacogenomic testing information in their drug labels. Pharmacogenomic testing was detected for 1.5% (129/8,718) of medication orders with recommended or required testing. Of the 3,817 medication orders associated with somatic pharmacogenomic testing information in their drug labels, 20% (372/1,819) of required tests were detected. The low rates of detectable pharmacogenomic testing suggest that structured testing programs are required to achieve the success of precision medicine.
Project description:Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing.To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20mg dose of baclofen approximately 110 min prior to scanning.Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p=0.001).Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the 'limbic' substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an 'as-needed' basis to block craving during 'at risk' situations.
Project description:Gamma-hydroxybutyrate (GHB) withdrawal is a life-threatening condition that does not always respond to standard treatment with benzodiazepines. Baclofen has potential utility as a pharmacological adjunct and anecdotal reports suggest that it is being used by drug users to self-manage GHB withdrawal symptoms. Here, we investigate current patterns of use and the online availably of baclofen.Data triangulation techniques were applied to published scientific literature and publicly accessible Internet resources (grey literature) to assess the use of baclofen in GHB withdrawal. An Internet snapshot survey was performed to identify the availability of baclofen for online purchase and the compliance of retailers with the UK regulations. Data were collected according to pre-defined criteria.A total of 37 cases of baclofen use in GHB withdrawal were identified in the scientific literature, as well as 51 relevant discussion threads across eight Internet forums in the grey literature. Baclofen was available to purchase from 38 online pharmacies, of which only one conformed to the UK regulations.There is limited published evidence on the use of baclofen in GHB withdrawal, but both scientific and grey literature suggests clinical utility. Online pharmacies are readily offering prescription-only-medication without prescription and due to inadequate regulation, pose a danger to the public.
Project description:Baclofen has been suggested as a potential pharmacotherapy for alcohol use disorder, but the clinical data are conflicting. Here we investigated the biobehavioral effects of baclofen in a sample of anxious alcohol-dependent individuals. This was a randomized, double-blind, placebo-controlled, human laboratory study in non-treatment seeking alcohol-dependent individuals with high trait anxiety (N=34). Participants received baclofen (30 mg per day) or placebo for at least 8 days, then performed an experimental session consisting of alcohol cue-reactivity followed by alcohol administration procedure (alcohol priming, then alcohol self-administration). Total amount of alcohol self-administered was the primary outcome; alcohol craving, subjective/physiological responses and mood/anxiety symptoms were also evaluated. There was no significant medication effect on the total amount of alcohol consumed during the alcohol self-administration (P=0.76). Baclofen blunted the positive association between maximum breath alcohol concentration during priming and the amount of alcohol consumption (significant interaction, P=0.03). Ratings of feeling intoxicated were significantly higher in the baclofen group after consuming the priming drink (P=0.006). During the self-administration session, baclofen significantly increased ratings of feeling high (P=0.01) and intoxicated (P=0.01). A significant reduction in heart rate (P<0.001) and a trend-level increase in diastolic blood pressure (P=0.06) were also detected in the baclofen group during the alcohol laboratory session. In conclusion, baclofen was shown to affect subjective and physiological responses to alcohol drinking in anxious alcohol-dependent individuals. These results do not support an anti-craving or anti-reinforcing effect of baclofen, but rather suggest that baclofen may act as a substitution medication for alcohol use disorder.