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

Pharmacokinetics Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05257447
• Other study ID #: STU2021-0797
• Status: Completed
• Phase: Phase 1
• Start date: April 27, 2022
• Est. completion date: December 13, 2022

Study information

• Verified date: March 2023
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 13, 2022
• Est. primary completion date: December 13, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Pharmacokinetics

Intervention

Drug:
• Baclofen 20 mg Tablet
Single oral dose given at approximately 8 AM on day of visit, with 6-8 ounces of tap water.
• Chlorzoxazone 500 mg Tablet
Single oral dose given at approximately 8 AM on day of visit, with 6-8 ounces of tap water.
• 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.

Locations

Country	Name	City	State
United States	UT Southwestern Medical Center	Dallas	Texas

Sponsors (2)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	Tufts University

Country where clinical trial is conducted

United States, 

References & Publications (18)

Agarwal SK, Kriel RL, Cloyd JC, Coles LD, Scherkenbach LA, Tobin MH, Krach LE. A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers. J Child Neurol. 2015 Jan;30(1):37-41. doi: 10.1177/0883073814535504. Epub 2014 Jul 14. — View Citation

Court MH, Von Moltke LL, Shader RI, Greenblatt DJ. Biotransformation of chlorzoxazone by hepatic microsomes from humans and ten other mammalian species. Biopharm Drug Dispos. 1997 Apr;18(3):213-26. doi: 10.1002/(sici)1099-081x(199704)18:33.0.co;2-0. — View Citation

Ernstgard L, Warholm M, Johanson G. Robustness of chlorzoxazone as an in vivo measure of cytochrome P450 2E1 activity. Br J Clin Pharmacol. 2004 Aug;58(2):190-200. doi: 10.1111/j.1365-2125.2004.02132.x. — View Citation

Greenblatt DJ, Abourjaily PN. Pharmacokinetics and Pharmacodynamics for Medical Students: A Proposed Course Outline. J Clin Pharmacol. 2016 Oct;56(10):1180-95. doi: 10.1002/jcph.732. Epub 2016 May 9. No abstract available. — View Citation

He J, Li N, Xu J, Zhu J, Yu Y, Chen X, Lu Y. An LC-MS/MS Validated Method for Quantification of Chlorzoxazone in Human Plasma and Its Application to a Bioequivalence Study. J Chromatogr Sci. 2019 Aug 16;57(8):751-757. doi: 10.1093/chromsci/bmz052. — View Citation

He Q, Chhonker YS, McLaughlin MJ, Murry DJ. Simultaneous Quantitation of S(+)- and R(-)-Baclofen and Its Metabolite in Human Plasma and Cerebrospinal Fluid using LC-APCI-MS/MS: An Application for Clinical Studies. Molecules. 2020 Jan 8;25(2):250. doi: 10.3390/molecules25020250. — View Citation

Hohmann N, Blank A, Burhenne J, Suzuki Y, Mikus G, Haefeli WE. Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses. Br J Clin Pharmacol. 2019 Oct;85(10):2310-2320. doi: 10.1111/bcp.14040. Epub 2019 Aug 9. — View Citation

Johnson-Agbakwu C, Brown L, Yuan J, Kissling R, Greenblatt DJ. Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study. Clin Ther. 2018 Jan;40(1):64-73. doi: 10.1016/j.clinthera.2017.08.021. Epub 2017 Dec 2. — View Citation

Lal R, Sukbuntherng J, Tai EH, Upadhyay S, Yao F, Warren MS, Luo W, Bu L, Nguyen S, Zamora J, Peng G, Dias T, Bao Y, Ludwikow M, Phan T, Scheuerman RA, Yan H, Gao M, Wu QQ, Annamalai T, Raillard SP, Koller K, Gallop MA, Cundy KC. Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J Pharmacol Exp Ther. 2009 Sep;330(3):911-21. doi: 10.1124/jpet.108.149773. Epub 2009 Jun 5. — View Citation

Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, Berthou F. Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics. 1999 Jun;9(3):377-88. doi: 10.1097/00008571-199906000-00013. — View Citation

Mishin VM, Rosman AS, Basu P, Kessova I, Oneta CM, Lieber CS. Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans. Am J Gastroenterol. 1998 Nov;93(11):2154-61. doi: 10.1111/j.1572-0241.1998.00612.x. — View Citation

Noe DA. Parameter Estimation and Reporting in Noncompartmental Analysis of Clinical Pharmacokinetic Data. Clin Pharmacol Drug Dev. 2020 Jul;9 Suppl 1:S5-S35. doi: 10.1002/cpdd.810. — View Citation

Schmitz NS, Krach LE, Coles LD, Mishra U, Agarwal SK, Cloyd JC, Kriel RL. A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics. PM R. 2017 Aug;9(8):743-750. doi: 10.1016/j.pmrj.2016.11.002. Epub 2016 Nov 17. — View Citation

Simon N, Franchitto N, Rolland B. Pharmacokinetic Studies of Baclofen Are Not Sufficient to Establish an Optimized Dosage for Management of Alcohol Disorder. Front Psychiatry. 2018 Oct 5;9:485. doi: 10.3389/fpsyt.2018.00485. eCollection 2018. — View Citation

Streetman DS, Bertino JS Jr, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics. 2000 Apr;10(3):187-216. doi: 10.1097/00008571-200004000-00001. — View Citation

Valicherla GR, Mishra A, Lenkalapelly S, Jillela B, Francis FM, Rajagopalan L, Srivastava P. Investigation of the inhibition of eight major human cytochrome P450 isozymes by a probe substrate cocktail in vitro with emphasis on CYP2E1. Xenobiotica. 2019 Dec;49(12):1396-1402. doi: 10.1080/00498254.2019.1581301. Epub 2019 Jun 19. — View Citation

Vlavonou R, Perreault MM, Barriere O, Shink E, Tremblay PO, Larouche R, Pichette V, Tanguay M. Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations. J Clin Pharmacol. 2014 May;54(5):584-92. doi: 10.1002/jcph.247. Epub 2014 Jan 10. — View Citation

Zhao Y, Harmatz JS, Epstein CR, Nakagawa Y, Kurosaki C, Nakamura T, Kadota T, Giesing D, Court MH, Greenblatt DJ. Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen. Br J Clin Pharmacol. 2015 Nov;80(5):1076-85. doi: 10.1111/bcp.12644. Epub 2015 Jun 8. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of adverse events reported as mild, moderate, or severe	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
Primary	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
Primary	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