Steady-state pharmacokinetics of once-daily cyclobenzaprine extended release: a randomized, double-blind, 2-period crossover study in healthy volunteers.
Author(s): Darwish M, Hellriegel ET
Affiliation(s): Department of Clinical Pharmacology, Cephalon, Inc, Frazer, Pennsylvania. email@example.com
Publication date & source: 2011-06, Clin Ther., 33(6):746-53.
Publication type: Comparative Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
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 (AUC(0-tau,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((1/2))). 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 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((1/2)) 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%). 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 (c) 2011 Elsevier HS Journals, Inc. All rights reserved.