Formulation and Evaluation of Baclofen-Meloxicam Orally Disintegrating Tablets (ODTs) Using Co-Processed Excipients and Improvement of ODTs Performance Using Six Sigma Method.

PURPOSE: This study aimed to formulate an orally disintegrating tablet (ODT) containing both baclofen and meloxicam together for treating osteoarthritis. METHODS: Direct compression method was used to prepare ODTs using three types of co-processed excipients (Prosolv ODT G2®, F-melt®, and Pharmaburst®500). ODTs were evaluated according to weight variation, thickness, friability, hardness, drug content, wetting time, in-vitro disintegration time, in-vitro dissolution test, and palatability. To enhance the in-vitro dissolution of meloxicam and palatability of ODT, a six sigma methodology was used, and an improvement phase was established where ODTs were prepared using lyophilization and levigation techniques. Finally, a pharmacokinetic study of the improved ODT was accomplished in comparison to the conventional oral tablet. RESULTS: Pharmaburst-based formula (F4) showed the shortest wetting time and, consequently, the shortest disintegration time and the highest percentage of drug dissolved within 3 min compared to the other formulae. All the improved ODTs had a bitterness taste score vary from (0) palatable and (+1) tasteless. The current sigma level was 3.628 σ and 3.33 σ for palatability and solubility of ODT, respectively, which indicated the process was successfully improved compared with the previous sigma level of 2.342 σ of both processes. Pharmacokinetic study of the improved ODTs showed a significant decrease of Tmax to 120 and 30 min instead of 180 and 120 min for meloxicam and baclofen, respectively. CONCLUSION: ODTs were successfully improved using the six sigma methodology, the pharmacokinetic parameters of both drugs were enhanced due to rapid absorption through the oral mucosa.

Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen.

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics. Baclofen, an intrathecally administered drug to treat spasticity, was used as a proof-of-principle xenobiotic. An in vitro blood-brain barrier (BBB) model was used to determine the BBB permeability of baclofen needed to simulate plasma and cerebrospinal concentrations. Simulated baclofen concentrations in individuals and populations of adults and children generally fall within 2-fold of measured clinical study concentrations. Further, in vitro micro-electrode array recordings were used to determine the effect of baclofen on neuronal activity (cell signalling). Using quantitative in vitro-in vivo extrapolations (QIVIVE) corresponding doses of baclofen were estimated. QIVIVE showed that up to 4600 times lower intrathecal doses than oral and intravenous doses induce comparable neurological effects. Most simulated doses were in the range of administered doses. This show that PBK models predict concentrations in the central nervous system for various routes of administration accurately without the need for additional in vivo data.

Removal of baclofen with hemodialysis is negligible compared to intact kidney excretion in a pediatric overdose: a case report.

INTRODUCTION: Severe baclofen toxicity can result in respiratory failure, hemodynamic instability, bradycardia, hypothermia, seizures, coma, and death. While hemodialysis (HD) is well-described in treating acute baclofen toxicity in patients with end-stage kidney disease or acute kidney injury, the utility of HD for patients with normal kidney function is uncertain. Implementing HD to speed recovery after a large acute baclofen ingestion is appealing, considering: (a) potential for prolonged coma and ventilator-associated morbidity, and (b) baclofen's low protein-binding, low molecular-weight, and moderate volume of distribution. METHODS: We report a 51 kg, 14-year-old girl who presented to the emergency department (ED) with hypotension, obtundation, and status epilepticus after an intentional ingestion of 1200 mg baclofen. Her post-intubation neurologic examination was concerning for coma. A 14-hour post-ingestion baclofen concentration was 882 ng/mL (therapeutic range 80-400 ng/mL). Three urgent-HD sessions were performed to reduce her time on the ventilator. RESULTS: The total baclofen removed in the first three-hour HD session was 3.05 mg. The total urinary elimination of baclofen 42 mg over 24-hours on day one. She was discharged without neurologic deficits to psychiatry on day-14. CONCLUSION: In this case, the amount of baclofen recovered during HD is negligible in comparison to the amount cleared by kidney elimination in this patient with normal kidney function.

Design, characterization and in vivo evaluation of modified release baclofen floating coated beads.

Baclofen is a centrally acting skeletal muscle relaxant approved by the US Food and Drug Administration (FDA) for the treatment of muscle spasticity, but the immediate release mode of administration and rapid absorption has been associated with adverse effects. The main objective of this study was to prepare modified release floating beads of baclofen in order to decrease the unwanted side effects. The beads were prepared using alginate and coated with Eudragit RS100, Eudragit L100 and cetyl alcohol. They were evaluated for their encapsulation efficiency, buoyance characteristics, morphology, and in vitro release. They have also been tested in vivo for their oral bioavailability and potential side effects. The prepared beads showed floating properties up to 12 h with different lag times ranging from 45.67 to 72.33 sec. Morphological evaluation using scanning electron microscopy (SEM) revealed that the coated beads show smooth with no pores or cracks surfaces. Real-time morphology of the beads during in vitro release testing was studied by the SEM. Optimized formulation of baclofen coated beads exhibited favorable mechanical properties, in addition, it provided extended baclofen release for up to 6 h. In addition, in vivo studies showed that the coated beads effectively decreased the hypotensive side effect associated with rapid plasma peaking from Baclofen® immediate-release tablets. In addition, there were significant differences between the values of Cmax, Tmax, and AUC0-24 of optimized modified release baclofen floating formulations when compared to Baclofen® immediate-release tablets.

Brain GABA levels are reduced in alcoholic liver disease: A proton magnetic resonance spectroscopy study.

BACKGROUND AND AIMS: Baclofen, a selective γ-aminobutyric acid (GABA)B receptor agonist, has emerged as a potential treatment for alcohol use disorder with much unexplained variation in response to treatment efficacy and dose regimen. Several positive studies include patients with alcoholic liver disease (ALD) and/or history of heavy drinking. The aim of this paper was to examine the association of cortical GABA+ concentration with severity of liver disease (including markers of liver injury) and other clinical characteristics in alcohol patients. METHODS: Proton magnetic resonance spectroscopy (1 H-MRS), from the parietal lobe, was analyzed to yield absolute concentration of GABA in 24 alcohol-dependent individuals. Diagnosis of ALD, markers of liver injury, severity of liver disease (Model for End-Stage Liver Disease [MELD]), and alcohol history were assessed. Covariates included concurrent medication, age, and recent alcohol consumption. RESULTS: Multiple linear regression revealed that GABA+ concentration was significantly predicted by MELD scores (F = 5.02, R2  = 0.59, P = 0.01; MELD: B = -0.63, P = 0.02), when controlling for covariates concurrent medication, age, and recent alcohol consumption. CONCLUSION: Severity of ALD is associated with lower cortical concentrations of GABA+. These results may explain variations in response to the GABAB agonist, baclofen, in the alcohol-dependent population.

Pharmacokinetics and toxicity of high-dose baclofen in ICU patients.

BACKGROUND: High-dose baclofen could prove beneficial in patients with unhealthy alcohol use in intensive care units (ICU). However, the pharmacokinetic properties of baclofen are unknown in this population. Our objectives were to investigate the pharmacokinetics of baclofen and the relationship between baclofen exposure and its toxicity in the ICU. MATERIALS AND METHODS: As part of a healthcare quality improvement project, we conducted a prospective, single-center study in a surgical intensive care unit at Nantes University Hospital in order to assess our local protocol of sedation in patients with consumption of alcohol above the recommended limits by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Baclofen pharmacokinetics were investigated by a non-compartment analysis and a population approach in 20 patients under mechanical ventilation. After a baclofen loading dose on day 1, daily doses were divided into 3 intakes adapted to glomerular filtration rate (GFR) and blood samples were withdrawn on day 3 for pharmacokinetic analysis. Baclofen was administered until extubation or tracheostomy and agitation-related events as well as the potential side effects of baclofen were noted. RESULTS: In this population, pharmacokinetic parameters [absorption latency time = 0.37 h, absorption constant rate = 2.2 h-1, apparent volume of distribution = 105 L, apparent clearance (l/h) = 13.5 × (GFR/103)0.839] were characterized by modified absorption and the influence of renal function: renal failure significantly increased baclofen exposure (p = .007) and significantly decreased baclofen clearance (p = .007) compared with patients without renal failure. When comparing patients with or without possible signs of baclofen toxicity, no difference was found regarding baclofen exposure (p = .34) and plasma peak concentration (p = .26). CONCLUSIONS: The a priori planned algorithm for dose adaptation according to renal clearance appeared to be suitable in our population. Daily administration of 150 mg of baclofen in ICU patients with preserved renal function did not lead to toxic concentrations in the plasma. A dose reduction of approximately 40%, 60% and 70% in patients with mild, moderate and severe renal failure could be suggested.

Baclofen-Loaded Poly (D,L-Lactide-Co-Glycolic Acid) Nanoparticles for Neuropathic Pain Management: In Vitro and In Vivo Evaluation.

In this work, poly (D,L-lactide-co-glycolic acid) (PLGA) nanoparticles of baclofen (Bcf-PLGA-NPs) were developed and optimized using nanoprecipitation method. The average particle size of the Bcf-PLGA-NP was found to be 124.8 nm, polydispersity index of 0.225, and zeta potential was found to be in the range of -20.4 mV. In vitro dissolution studies showed that Bcf was released from PLGA NPs in a sustained manner from 50% release in 2.5 hours to 80%-85% in 24 hours. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on Neuro-2a neuroblastoma cell line showed comparably low cytotoxicity of Bcf-PLGA-NPs as compared with aqueous solution of Bcf at reported Cmax values of the drug. To explore the nose-to-brain pathway, in vivo studies were carried out in Sprague-Dawley rats by radiolabeling of Bcf with technetium-99m (99mTc). Gamma scintigraphy images of the rats that were administered through intranasal (i.n.) route showed the maximum uptake of radiolabeled NPs from nose to brain at 3 hours as compared with the rats administered with NPs intravenously and orally. To assess the Bcf concentration in brain and blood, biodistribution studies were performed and following i.n. route the NPs were dispersed in brain (3.5%/g) and blood (3%/g) at 3 hours, and these observations were in agreement with the gamma scintigrams. Hence, from the results it was suggested that the developed PLGA NPs could serve as a potential carrier for the Bcf in the treatment of neuropathic pain.

Novel extended in vitro-in vivo correlation model for the development of extended-release formulations for baclofen: From formulation composition to in vivo pharmacokinetics.

In vitro-in vivo correlation (IVIVC), a predictive mathematical model between the in vitro dissolution and the in vivo pharmacokinetics has been utilized for the development of new extended release (ER) formulations. The aim of the present study was to extend the IVIVC approach, which correlates among the formulation composition, the in vitro dissolution, and the plasma drug concentration, to predict plasma drug concentrations from a given composition of the formulation, and vice versa, using baclofen as a model drug. Baclofen ER tablets with different dissolution rates were prepared by varying the composition of hydroxypropyl methylcellulose (HPMC). First, the HPMC compositions and the corresponding in vitro dissolutions parameters were correlated, and then the in vitro dissolution parameters were correlated with the in vivo dissolution parameters extracted from the pharmacokinetic profiles of the baclofen ER formulations via population pharmacokinetic modeling. The final extended IVIVC model linked the composition of the formulation, the in vitro dissolution, and the in vivo plasma concentration profile and was successfully applied for the prediction of in vivo pharmacokinetics from the amount of HPMC in baclofen ER formulations. The present approach holds great promise for designing optimal compositions of ER formulations to present desired plasma concentration profile.

Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome.

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (p <0.01), hypothermia (p <.001) and respiratory depression (p <.01) were altered in repeatedly baclofen-pretreated rats (p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (p <.01) and expiratory times (p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (p <.05) and absorption constant rate (p <.05) and reduced the distribution volume (p <.0001) and elimination half-life (p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.

Baclofen Toxicity in Kidney Disease.

Baclofen, a commonly prescribed muscle relaxant, is primarily excreted via the kidneys; toxicity is a potentially serious adverse outcome in patients with decreased kidney function. We describe a patient with end-stage kidney disease receiving hemodialysis who developed neurotoxicity and hemodynamic instability after receiving baclofen for muscle spasms. In this case, prompt recognition of baclofen toxicity and urgent hemodialysis were effective in reversing this toxicity. This case is used to examine the pharmacokinetics and pathophysiology of baclofen toxicity and discuss appropriate diagnosis and management of baclofen toxicity. We recommend reducing the baclofen dose in patients who have moderately reduced kidney function (estimated glomerular filtration rate, 30-60mL/min/1.73m2) and avoiding use in patients with severely reduced kidney function (estimated glomerular filtration rate < 30mL/min/1.73m2) or on renal replacement therapy.

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

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.

Population pharmacokinetics of oral baclofen at steady-state in alcoholic-dependent adult patients.

Baclofen has been proposed for few years to help treating alcohol dependence at higher doses than those used in neurology. Baclofen pharmacokinetics has been previously well described at low oral or intravenous doses but remains poorly investigated with such high oral doses. We here describe dose regimens of baclofen in 143 alcohol-dependent patients treated with steady-state oral doses of baclofen. Plasma baclofen levels were measured in blood samples using liquid chromatography coupled with tandem mass spectrometry. One hundred and forty-nine baclofen concentrations were sampled 30 min to 15 h after the last dose, and baclofen pharmacokinetics was determined using population pharmacokinetics approach. Our population, whose average age and BMI were 51.5 years and 25.5 kg/m2 , respectively, was composed of two-thirds of men. Daily baclofen doses ranged from 15 to 250 mg and 26% were higher than 120 mg. A one-compartment model with first-order absorption and elimination allowed to determine mean values for clearance (CL/F), volume of distribution (V/F) and absorption rate constant at 8.0 L/h, 44.5 L and 2.23 h-1 , respectively. Inter-individual variability on CL/F and V/F was 27.4 and 86% for the parameters. None of the demographic and biological covariates significantly decreased inter-individual variability. A proportional relationship between oral dose and plasma baclofen exposure indicated a linear pharmacokinetics of baclofen even at doses over 120 mg/day. Our large population study evidenced a linear pharmacokinetics of oral baclofen even at high daily doses with an inter-individual variability of baclofen exposure that could not be explained by demographic and biological data.

A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics.

BACKGROUND: Abrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome. OBJECTIVE: To evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses. DESIGN: Randomized, open-label, dose-escalation, crossover study. SETTING: Contract Research Organization (CRO). METHODS: Three cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period. MAIN OUTCOME MEASURES: Subjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography-mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis. RESULTS: None of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (Cmax). After the 20 mg PO and 15 mg IV doses, mean Cmax levels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%. CONCLUSIONS: All PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible. LEVEL OF EVIDENCE: II.

Pharmacokinetic comparison and bioequivalence evaluation of two 10-mg baclofen formulations in healthy male subjects
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BACKGROUNDS: Baclofen is used as a skeletal muscle relaxant for multiple sclerosis patients. It depresses the transmission of monosynaptic and polysynaptic reflex by stimulating GABAß (gamma-aminobutyric acid) receptors. OBJECTIVES: The aim of this study was to compare the pharmacokinetic characteristics of two 10-mg baclofen formulations and to assess bioequivalence. METHODS: A randomized, single-dose, two-period, two-sequence crossover study was conducted in healthy male subjects. Each subject received the test or reference formulations. After washout period, all subjects received the alternative formulation. Blood samples were collected for up to 24 hours after the dose in each period. Pharmacokinetic (PK) parameters, including tmax, Cmax, and AUClast were calculated by noncompartmental methods. The geometric mean ratio (GMR) of the test to the reference formulation and its 90% confidence interval (CI) for Cmax and AUClast were calculated for assessment of bioequivalence. RESULTS: A total of 22 subjects completed the study. The median tmax of the test and the reference formulation were 1.50 and 1.25 hours, respectively. The mean (± SD) Cmax of the test and the reference formulation were 141.401 ± 29.447 ng/mL and 138.837 ± 31.392 ng/mL, respectively. The mean (± SD) AUClast of the two formulations were 702.404 ± 82.149 ng×h/mL and 726.803 ± 90.638 ng×h/mL, respectively. The GMR (90% CI) of the test to the reference formulation for the Cmax and AUClast were 1.0306 (0.9564 - 1.1106) and 0.9674 (0.9437 - 0.9916), respectively. CONCLUSIONS: The two different baclofen 10-mg formulations had similar PK profiles and were bioequivalent based on Cmax and AUClast.
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Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats.

BACKGROUND AND PURPOSE: While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity. EXPERIMENTAL APPROACH: Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg(-1) , p.o.) at 4 h intervals and baclofen-mediated changes in parameters recorded. A pharmacokinetic-pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats. KEY RESULTS: Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR. CONCLUSIONS AND IMPLICATIONS: The systems pharmacology model developed fits baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances.

A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity.

AIMS: Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB. METHODS: Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 µg and an optional dose of 100 µg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model. RESULTS: All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 µg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model. CONCLUSIONS: ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.

Baclofen novel gastroretentive extended release gellan gum superporous hydrogel hybrid system: in vitro and in vivo evaluation.

Baclofen is a centrally acting skeletal muscle relaxant with a short elimination half-life, which results in frequent daily dosing and subsequent poor patient compliance. The narrow absorption window of baclofen in the upper gastrointestinal tract limits its formulation as extended release dosage forms. In this study, baclofen extended release superporous hydrogel (SPH) systems, including conventional SPH, SPH composite and SPH hybrid (SPHH), were prepared aiming to increase the residence of baclofen at its absorption window. The applicability of different polymers, namely, gellan gum, guar gum, polyvinyl alcohol and gelatin, was investigated in preparation of SPHH systems. The prepared SPH systems were evaluated regarding weight and volume swelling ratio, porosity, mechanical properties, incorporation efficiency, degree of erosion and drug release. In vivo assessment was performed in dogs to evaluate gastric residence time by X-ray studies. In addition, the oral bioavailability of baclofen relative to commercially available Lioresal® immediate release tablets was also investigated. The novel baclofen gellan SPHH cross linked with calcium chloride was characterized by optimum mechanical properties, acceptable swelling properties as well as extended drug release. It also exhibited a prolonged plasma profile when compared to twice daily administered Lioresal®.