Pharmacokinetic and Bioequivalence Comparison of Baclofen and Chlorzoxazone Administered Individually or Concurrently

Study Overview
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Brief Summary
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Combination treatment with baclofen and chlorzoxazone (CHZ) is under investigation for the treatment of spinocerebellar ataxia types 1 and 2. Achievement of therapeutic benefit with this combination approach requires that effective concentrations of both agents reach the systemic circulation, and ultimately reach the intended pharmacologic target. This in turn requires understanding of the clinical pharmacokinetic properties of both drugs when administered individually, as well as knowledge of the extent to which the agents might interact when given concurrently. Study Objectives: To evaluate the pharmacokinetic properties of baclofen and CHZ when administered as individual entities at separate times, using customary clinical doses. To compare the pharmacokinetic properties, and assess the bioequivalence, of each drug administered separately compared to administration of the two drugs concurrently. To assess adverse events attributed to the two drugs when administered separately or together.

Detailed Description
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Baclofen has been available for clinical use in the United States since 1977 and is used for the treatment of spasticity arising from a variety of causes. Oral baclofen can be administered in tablet form or as a solution. Comparison of the kinetics of IV and oral baclofen indicates that absolute bioavailability is in the range of 75%. Clearance of S-baclofen, the pharmacologically active enantiomer, occurs mainly by renal excretion of the intact drug. A small fraction of the administered R-enantiomer is also biotransformed by deamination. In individuals with normal renal function, the elimination half-life is in the range of 3 to 6 hours. Clearance is reduced and half-life is prolonged when renal function is impaired. Baclofen pharmacokinetics are linear (dose-independent), in that half-life and clearance are fixed regardless of the administered dose, or duration of treatment. Chlorzoxazone (CHZ) has been in clinical use since 1988 and is described as a skeletal muscle relaxant. The principal metabolic pathway of CHZ involves hydroxylation by the hepatic enzyme Cytochrome P450-2E1 (CYP2E1), yielding the major metabolite 6-OH-CHZ. As a substrate for the single enzyme isoform CYP2E1, CHZ has become extensively used in drug development and clinical pharmacology as an in vivo probe or index compound to profile human CYP2E1 metabolic phenotype, based on systemic clearance or area under the plasma concentration curve (AUC) after a single test dose. In healthy individuals, the elimination half-life of CHZ falls in the range of 0.7 to 2.0 hours. With this short half-life, a pharmacokinetic study can be completed using a sampling period of 12 hours after a single dose. The study will have a randomized, single-dose, 3-way crossover design, with at least one week elapsing between the 3 trials of the study. The sequence of administration is based on a randomization code. Venous blood samples are drawn prior to the dose, and at specified time points during 24 hours after the dose. Concentrations of baclofen and/or chlorzoxazone are determined in each sample, and customary pharmacokinetic analyses are used to evaluate kinetic properties, and bioequivalence between individual versus combined administration of the two drugs. Candidates for participation will come to the study site for an interview and screening evaluation. Screening procedures will include medical history, medication use (including non-prescription and herbal), physical examination, blood hematology and clinical chemistry, blood immunology screen (HIV and hepatitis), urinalysis, urine drug screen, and serum pregnancy test (for potentially childbearing female participants). Screening data for each subject is reviewed by the Principal Investigator through a global evaluation of all information. The PI then decides whether participation would be safe and reasonable. The PI can choose to decline a candidate's approval as a study subject if the available information indicates that participation would be unsafe or inappropriate. Subjects arrive at the study unit at 7 AM on each of the three study trial days, following an overnight fast. They are provided with a light breakfast on arrival. Peripheral venous sampling access is established via an indwelling catheter, connected to intravenous fluid (D5W or normal saline) at a keep open rate. A heparin lock can also be used - this is flushed with dilute heparin (5 Units per mL) after each sample is drawn. Venous blood samples (7 mL each) are drawn from the indwelling catheter into heparinized (green-top) tubes prior to dosage, and at the following post-dosage times: 1, 2, 3, 4, 6, 8, 10, and 12 hours. Subjects return to the study unit at 8 AM the following morning, at which time a 24-hour PK sample and repeat hematology and chemistry is drawn. The PI or designate will conduct a structured interview to evaluate the occurrence of adverse events Plasma concentrations of baclofen or chlorzoxazone, as appropriate, will be determined by liquid chromatography-mass spectrometry using contemporary methodology which has been validated, and conforms to customary regulatory standards for sensitivity, specificity, replicability, precision, and accuracy. All samples from a given subject's set of 3 trials will be extracted and analyzed on the same day using the same calibration standards by Tufts University.

Official Title
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Pharmacokinetic and Bioequivalence Comparison of Baclofen and Chlorzoxazone When Administered Individually or Concurrently

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: Baclofen 20 mg Tablet
* Drug: Chlorzoxazone 500 mg Tablet
* Drug: Baclofen 20mg tablet and Chlorzoxazone 500 mg tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or female Ages 18 to 55 years of age Ambulatory Non-smoker No current or past history of significant medical or psychiatric disease Not currently taking prescription medications or on a regular or recurrent basis Exclusion Criteria: Non-ambulatory Smokers Current or past history of significant medical or psychiatric disease Currently taking prescription medications or taking on a regular or recurrent basis Available information about potential participant indicates that participation would not be safe or appropriate, per PI discretion

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study will have a randomized, single-dose, 3-way crossover design, with at least one week elapsing between the 3 trials of the study. The sequence of administration is based on a randomization code.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baclofen 20mg tablet<br>Single oral dose of baclofen, 20 mg | Drug: Baclofen 20 mg Tablet<br>* Single oral dose given at approximately 8 AM on day of visit, with 6-8 ounces of tap water.<br>|
| Experimental: Chlorzoxazone 500mg tablet<br>Single oral dose of chlorzoxazone, 500 mg | Drug: Chlorzoxazone 500 mg Tablet<br>* Single oral dose given at approximately 8 AM on day of visit, with 6-8 ounces of tap water.<br>|
| Experimental: Baclofen 20 mg tablet and chlorzoxazone 500 mg tablet<br>Concurrent doses of baclofen, 20 mg, and chlorzoxazone, 500 mg | Drug: Baclofen 20mg tablet and Chlorzoxazone 500 mg tablet<br>* Concurrent single oral dose given at approximately 8 AM on day of visit, with 6-8 ounces of tap water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the maximum measured plasma concentration (Cmax) of baclofen or chlorzoxazone administered separately with baclofen-chlorzoxazone administered concurrently. | Compare the pharmacokinetic properties and assess bioequivalence of baclofen and chlorzoxazone administered separately compared to baclofen-chlorzoxazone administered concurrently, determined by liquid chromatography-mass spectrometry. Maximum measured plasma concentration (Cmax) will be reported. | Pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose | 
| Compare the area Under the Plasma Concentration Versus Time Curve (AUC) of baclofen and chlorzoxazone administered separately with baclofen-chlorzoxazone administered concurrently. | Evaluate the pharmacokinetic properties of baclofen and chlorzoxazone administered individually, determined by liquid chromatography-mass spectrometry with baclofen-chlorzoxazone administered concurrently. Area under the plasma concentration curve until the last non-zero concentration (AUC-last) will be reported. | Pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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baclofen, chlorzoxazone, pharmacokinetics