Single- and multiple-dose bioequivalence of two once-daily tramadol formulations using stereospecific analysis of tramadol and its demethylated (M1 and M5) metabolites.

Author(s): Eradiri O, Sista S, Lai JC, Nguyen OH, Silverstone PH

Affiliation(s): Biovail Technologies Ltd., Chantilly, VA 20151, USA. okpo.eradiri@biovail.com

Publication date & source: 2007-07, Curr Med Res Opin., 23(7):1593-604.

Publication type: Research Support, Non-U.S. Gov't

OBJECTIVE: To assess bioequivalence of two once-daily formulations of tramadol (T) as well as delineate pharmacokinetics of its enantiomers and those of its main metabolites after single- and multiple-dose administration. METHODS: Single- and multiple-dose studies were conducted separately each in 48 healthy volunteers using an open-label, randomized, crossover design. Subjects received the 200 mg test (Tramadolor) and reference (Ultram ER) formulations in a randomized manner separated by a 7-day washout period once (single-dose study) or once daily for 7 days (multiple-dose study). Blood was sampled on days 1-2 (single-dose) or days 4-7 (multiple-dose), and plasma samples were analyzed using a stereospecific assay for quantitation of individual enantiomers of T and its active O-demethylated (M1) and N,O-demethylated (M5) metabolites. Bioequivalence was assessed using log-transformation and 90% confidence intervals. RESULTS: All analytes showed stereoselectivity after single and multiple doses of both products, with average concentrations of (+)-T, (-)-M1, and (-)-M5 exceeding those of their respective antipode. However, a decrease in steady-state oral clearance of T relative to single dose was not stereoselective. In both studies, the formulations were bioequivalent with regard to AUG and Cmax for both enantiomers of all analytes. The Tmax for the reference (10-12 h) was significantly (p < 0.05) longer than that for the test (5-6 h). Degree of fluctuation of T enantiomers after the test was greater than the reference. Both formulations were tolerated relatively well. CONCLUSIONS: Tramadolor and Ultram ER were bioequivalent for both enantiomers of T, M1 and M5. It is unlikely there would be any significant clinical differences between the two formulations.