Mona Darwish1, Edward T Hellriegel. 1. Department of Clinical Pharmacology, Cephalon, Inc, Frazer, Pennsylvania. mdarwish@cephalon.com
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.
RCT Entities:
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: Tatiane Maria de Lima Souza Brioschi; Simone Grigoleto Schramm; Eunice Kazue Kano; Eunice Emiko Mori Koono; Ting Hui Ching; Cristina Helena Dos Reis Serra; Valentina Porta Journal: Biomed Res Int Date: 2013-09-16 Impact factor: 3.411
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Authors: Andy Wolff; Revan Kumar Joshi; Jörgen Ekström; Doron Aframian; Anne Marie Lynge Pedersen; Gordon Proctor; Nagamani Narayana; Alessandro Villa; Ying Wai Sia; Ardita Aliko; Richard McGowan; Alexander Ross Kerr; Siri Beier Jensen; Arjan Vissink; Colin Dawes Journal: Drugs R D Date: 2017-03