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

Abstract: Background: 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. Objective: 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. Methods: 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 (AUC0–τ,ss), peak plasma cyclobenzaprine concentration (Cmax,ss), time to observed Cmax (Tmax,ss), observed minimum cyclobenzaprine concentration (Cmin,ss), average cyclobenzaprine concentration (Cavg,ss), accumulation ratio (Rac), and terminal elimination half-life (t½). Tolerability and safety assessments were conducted. Results: 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 Cmax,ss, Cmin,ss, and Cavg,ss were 41.1, 21.4, and 31.4 ng/mL, respectively. The median Tmax,ss for CER 30 mg was 7.0 hours, with a mean t½ 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 Rac 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%). Conclusions: 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. [Copyright &y& Elsevier]