Bioequivalence evaluation of single doses of two tramadol formulations: A randomized, open-label, two-period: Crossover study in healthy brazilian volunteers

Abstract

Background: Tramadol is a well tolerated and effective analgesic used to treat moderate to severe pain. Several generic formulations of tramadol are available in Brazil; however, published information regarding their bioequivalence in the Brazilian population is not available. A study was designed for Brazilian regulatory authorities to allow marketing of a generic formulation. Objective: The purpose of this study was to compare the bioequivalence of 2 commercial tablet preparations containing tramadol 100 mg marketed for use in Brazil. Methods: A randomized, open-label, 2 × 2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a washout period of 12 days. Two tablet formulations of tramadol 100 mg (test and reference formulations) were administered as a single oral dose, and blood samples were collected over 24 hours. Tramadol plasma concentrations were quantified using a validated HPLC method. A plasma concentration-time profile was generated for each volunteer and then mean values were determined, from which C max, T max, AUC 0−∞ k e, and t 1/2 were calculated using a noncompartmental model. Bioequivalence between the products was determined by calculating 90% CIs for the ratios of C max AUC 0−t and AUC0 −∞, values for the test and reference products using log-transformed data. Tolerability was assessed by monitoring vital signs (temperature, blood pressure, heart rate), laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and interviews with the volunteers before medication administration and every 2 hours during the study. Results: Twenty-six healthy volunteers (13 men, 13 women) were enrolled in and completed the study. Mean (SD) age was 30 (6.8) years (range, 21–44 years), mean weight was 64 (8.3) kg (range, 53–79 kg), and mean height was 166 (6.4) cm (range, 155–178 cm). The 90% CIs for the ratios of Cmax (1.01–1.17), AUC 0−t (1.00–1.13), and AUC 0−∞. (1.00–1.14) values for the test and reference products fell within the interval of 0.80 to 1.25 proposed by most regulatory agencies, including the Brazilian regulatory body. No clinically important adverse effects were reported; only mild somnolence was reported by 4 volunteers and mild headaches by 5 volunteers, and there was no need to use medication to treat these symptoms. Conclusion: Pharmacokinetic analysis in these healthy Brazilian volunteers suggested that the test and reference formulations of tramadol 100-mg tablets met the regulatory requirements to assume bioequivalence based on the Brazilian regulatory definition.