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

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 ERt) 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 NO-demethylated (W) 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, H-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 AUC and C-max. for both enantiomers of all analytes. The T 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.