Comparison of the Single-Dose Pharmacokinetics of Once-Daily Cyclobenzaprine Extended-Release 30 mg and Cyclobenzaprine Immediate-Release 10 mg Three Times Daily in the Elderly

Abstract

The clinical utility of cyclobenzaprine for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions is limited by cholinergic adverse effects associated with its use. As expected, these effects may be pronounced in the elderly in whom altered renal and hepatic function may change drug pharmacokinetics. The goal of this study was to characterize the pharmacokinetics of the extended-release formulation of cyclobenzaprine (CER) in elderly volunteers. This randomized, open-label, two-period crossover study compared the pharmacokinetics, safety and tolerability of a single oral 30-mg dose of CER with those of 10 mg of cyclobenzaprine immediate-release (CIR) administered every 8 hours for a total of three doses in 18 healthy volunteers aged 65-75 years. Volunteers were assigned to either CER or CIR on days 1 and 15 (separated by a 14-day washout). Outcome measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours (AUC168) and infinity (AUC infinity), peak plasma cyclobenzaprine concentration (Cmax), time to observed Cmax (tmax) and terminal elimination half-life of cyclobenzaprine. Adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Eighteen subjects were randomized and completed the first treatment period; 17 completed both periods of the study. The pharmacokinetics of CER 30 mg were characterized by an absorption phase with a median t(max) of 8 hours compared with an initial peak for CIR (following the first dose) at about 5 hours. Plasma cyclobenzaprine concentrations at 5 hours were 13.6 ng/mL for CER and 11.0 ng/mL for CIR. Systemic cyclobenzaprine exposure (AUC168, AUC infinity and Cmax) was similar for a single dose of CER and three doses of CIR and met bioequivalence criteria. Most AEs were mild in intensity; the most common AE was somnolence. No serious AEs or discontinuations as a result of AEs were reported during the study. Once-daily CER 30 mg exhibited controlled release of cyclobenzaprine and resulted in systemic exposure similar to that of CIR in subjects aged 65-75 years.