Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults : a randomized, open-label, two-period crossover, single-centre study.
OBJECTIVE
Cyclobenzaprine immediate release (CIR) has shown efficacy in the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. An extended-release formulation of cyclobenzaprine (CER) has been developed to provide effective muscle spasm relief with once-daily dosing. The objective of this study was to compare the pharmacokinetics of CER and CIR.


METHODS
This was a single-centre study of 18 healthy young adults (aged 18-45 years). Healthy volunteers were assigned to receive either a single dose of CER 30 mg or three doses of CIR 10 mg on days 1 and 15 (separated by a 14-day washout) in an open-label, two-period crossover study. Pharmacokinetic parameters were monitored through 168 hours after the last dose in each dose period; adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Cyclobenzaprine was administered as a single oral 30 mg dose of CER or three 10 mg oral doses of CIR given every 8 hours over 24 hours. Statistical tests were conducted against a two-sided alternative hypothesis at a 0.05 level of significance with equivalence limits of 80% and 125%. Measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours and infinity, maximum plasma cyclobenzaprine concentration (C(max)), and time to observed C(max) (t(max)).


RESULTS
Eighteen subjects were randomized and 17 completed both periods of the study. CER exhibited a consistent concentration-time profile with a single peak, in contrast to the pharmacokinetic profile for CIR, which displayed multiple peaks and troughs over the 24-hour period. The pharmacokinetic profile of CER 30 mg was characterized by an absorption phase with a median t(max) of approximately 6 hours, compared with the initial peak of CIR (following the first dose) of about 4 hours. Mean plasma concentrations at 4 hours were comparable (12.1 ng/mL for CER; 12.4 ng/mL for CIR). Systemic cyclobenzaprine exposure (AUC and C(max)) was similar across both formulations. The C(max) for CER 30 mg was 19.2 ng/mL (median t(max) = 6 hours) and for CIR (following the third dose) was 18.1 ng/mL (median t(max) = 12 hours). All AEs were mild in intensity; the most common AE was somnolence.


CONCLUSIONS
The pharmacokinetic profile of once-daily CER reflected the mode of administration, providing a controlled release of cyclobenzaprine with sustained plasma concentrations, in contrast to the fluctuating profile of CIR. CER 30 mg once daily and CIR 10 mg three times daily resulted in comparable systemic exposures.
Darwish
Mona
M
Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
Hellriegel
Edward T
ET
Xie
Fang
F
D000328:Adult; D000639:Amitriptyline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D009125:Muscle Relaxants, Central; D000639:Amitriptyline; C004704:cyclobenzaprine