Steady-State Pharmacokinetics of Once-Daily Cyclobenzaprine Extended Release: A Randomized, Double-Blind, 2-Period Crossover Study in Healthy Volunteers

• Published in: Clinical therapeutics Vol. 33; no. 6; pp. 746 - 753
• Main Authors: Darwish, Mona, Hellriegel, Edward T.
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.06.2011; Elsevier; Elsevier Limited
• Subjects: Adult; Amitriptyline - administration & dosage; Amitriptyline - adverse effects; Amitriptyline - analogs & derivatives; Amitriptyline - pharmacokinetics; Antidepressive Agents, Tricyclic - administration & dosage; Antidepressive Agents, Tricyclic - adverse effects; Antidepressive Agents, Tricyclic - pharmacokinetics; Area Under Curve; Biological and medical sciences; Catheters; Cross-Over Studies; cyclobenzaprine; Delayed-Action Preparations; Double-Blind Method; Drug Administration Schedule; Drug dosages; Drug therapy; Female; Half-Life; Hepatitis; Humans; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; muscle spasm; once daily; pharmacokinetic profile; Pharmacology. Drug treatments; Plasma; skeletal muscle relaxant; steady state; Studies; Young Adult; steady state; muscle spasm; once daily; pharmacokinetic profile; skeletal muscle relaxant; cyclobenzaprine; Human; Healthy subject; Controlled release form; Muscle relaxant; Psychotropic; Tricyclic compound; Striated muscle; Crossover study; Randomization; Dosage form; Cyclobenzaprine; Double blind study; Spasm; Antidepressant agent; Single daily dose; Daily dose; Pharmacokinetics
• ISSN: 0149-2918; 1879-114X; 1879-114X
• DOI: 10.1016/j.clinthera.2011.05.045

The single-dose pharmacokinetic profile of cyclobenzaprine extended-release (CER) has been previously characterized and compared with the pharmacokinetics of cyclobenzaprine immediate-release (CIR) administered 3 times daily for 3 doses. The objective of this study was to characterize the multiple-dose pharmacokinetic properties of once-daily CER 30 mg and CIR 10 mg TID formulations in healthy volunteers. In this double-blind, single-center, 2-period crossover study, healthy subjects were randomized to dosing sequences with once-daily CER 30 mg or CIR 10 mg TID for 7 days. Subjects crossed over to the alternative regimen following a 14-day washout period. Pharmacokinetic assessments at steady state included area under the plasma cyclobenzaprine concentration–time curve over the dosing interval (AUC 0–τ,ss), peak plasma cyclobenzaprine concentration (C max,ss), time to observed C max (T max,ss), observed minimum cyclobenzaprine concentration (C min,ss), average cyclobenzaprine concentration (C avg,ss), accumulation ratio (R ac), and terminal elimination half-life (t ½). Tolerability and safety assessments were conducted. A total of 36 subjects were randomized; 34 completed both dosing periods (1 subject was lost to follow-up, 1 withdrew consent). Steady state was reached for CER 30 mg on day 7. Mean C max,ss, C min,ss, and C avg,ss were 41.1, 21.4, and 31.4 ng/mL, respectively. The median T max,ss for CER 30 mg was 7.0 hours, with a mean t ½ of 34.8 hours. At steady state, CER produced a sustained plasma cyclobenzaprine concentration with a single peak in plasma concentration during the 24-hour dose interval. The R ac for CER was 2.65. Because of a protocol violation (insufficient data), no steady-state pharmacokinetic assessments could be performed for CIR. Most adverse events were mild or moderate in intensity. Somnolence was the most frequently reported adverse event (100% of subjects) in those receiving CER, followed by dry mouth (58%), dizziness (19%), and headache (17%). Once-daily CER 30 mg delivered sustained plasma cyclobenzaprine levels over 24 hours at steady state. Owing to a protocol violation, steady-state pharmacokinetic properties for CIR could not be assessed.