title: 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 (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.
authors.affiliation: Department of Clinical Pharmacology, Cephalon, Inc, Frazer, Pennsylvania. mdarwish@cephalon.com
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Edward T
authors.initials: ET
authors.lastname: Hellriegel
mesh_terms: D000328:Adult; D000639:Amitriptyline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000929:Antidepressive Agents, Tricyclic; D003692:Delayed-Action Preparations; D000639:Amitriptyline; C004704:cyclobenzaprine