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

March 30, 2023 updated by: Vikram Shakkottai, University of Texas Southwestern Medical Center

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

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:

  1. To evaluate the pharmacokinetic properties of baclofen and CHZ when administered as individual entities at separate times, using customary clinical doses.
  2. To compare the pharmacokinetic properties, and assess the bioequivalence, of each drug administered separately compared to administration of the two drugs concurrently.
  3. To assess adverse events attributed to the two drugs when administered separately or together.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Dallas, Texas, United States, 75390
        • UT Southwestern Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 55 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

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.
Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose
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.
Time Frame: Pre-dose and 1, 2, 3, 4, 6, 8, 10, 12, 24 hours post-dose
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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of adverse events reported as mild, moderate, or severe
Time Frame: Visit 1 Day 1, Visit 1 Day 2, Visit 2 Day 1, Visit 2 Day 2, Visit 3, Day 1, Visit 3 Day 2
Number adverse events is assessed by structured interview conducted to evaluate the occurrence of adverse events. The intensity/ seriousness of the AE ranges from 1-3, where higher scores indicate worse outcome
Visit 1 Day 1, Visit 1 Day 2, Visit 2 Day 1, Visit 2 Day 2, Visit 3, Day 1, Visit 3 Day 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Texas Southwestern Medical Center

Collaborators

Tufts University

Investigators

  • Principal Investigator: Vikram Shakkottai, MD, PhD, UT Southwestern Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 27, 2022

Primary Completion (Actual)

December 13, 2022

Study Completion (Actual)

December 13, 2022

Study Registration Dates

First Submitted

February 15, 2022

First Submitted That Met QC Criteria

February 15, 2022

First Posted (Actual)

February 25, 2022

Study Record Updates

Last Update Posted (Actual)

March 31, 2023

Last Update Submitted That Met QC Criteria

March 30, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STU2021-0797

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported, after de-identification.

IPD Sharing Time Frame

Immediately following publication. No end date.

IPD Sharing Access Criteria

Researchers who provide a methodologically sound proposal should direct inquiries to vikram.shakkottai@utsouthwestern.edu. Data requestors may need to sign a data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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