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.
mdarwish@cephalon.com
Publication date & source: 2011, Clin Ther. , 33(6):746-53
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-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.
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(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%).
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.
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