Relative bioavailability and pharmacokinetics of a new sibutramine formulation in healthy male subjects: a randomized, open-label, two-period, comparative crossover study.

Background: Sibutramine is an orally administered, centrally acting antiobesity drug. Sibutramine hydrochloride monohydrate is the conventional formulation, whereas sibutramine mesylate hemihydrate is a newly developed formulation. Drugs formed from different salts may differ in their solubility profiles and dissolution rates, which may affect their rate of absorption and thus their onset, duration, and intensity of effect.

Objective: This study was conducted to compare the relative bioavailability and pharmacokinetics of the new sibutramine formulation (test) with those of the conventional formulation (reference).

Methods: : This was a single-center, randomized, open-label, 2-period, comparative crossover study in healthy male subjects. All subjects received a single 15-mg oral dose of sibutramine hydrochloride monohydrate (reference) and a single 17.3-mg oral dose of sibutramine mesylate hemihydrate (test), both containing 12.55 mg sibutramine base. The 2 doses were separated by a 2-week washout period. Blood samples for pharmacokinetic analysis were collected during a 72-hour period after treatment. Safety parameters were assessed, including adverse events, hematology and biochemistry, urinalysis, and electrocardiography. Plasma concentrations of the active metabolites of sibutramine (desmethylsibutramine [M1] and didesmethylsibutramine [M2]) were determined, and the pharmacokinetic characteristics of the 2 formulations were compared using noncompartmental analysis.

Results: Sixteen subjects (mean [SD] age, 24.3 [2.3] years [range, 20-25 years]; mean [SD] body weight, 66.1 [5.1] kg [range, 57-77 kg]) were enrolled in and completed the study. The plasma concentration-time profiles of M1 and M2 were similar after administration of both formulations. The reference and test formulations showed pharmacokinetic equivalence with respect to M1 and M2. The relative bioavailability of the test drug was 117.6% for M1 and 102.4% for M2. The 90% Cls for the ratios of the log-transformed C(max) and AUC values were within the predetermined equivalence range of 80% to 125%. There were no significant changes in physical, biochemical, hematologic, or urinalysis variables during the study. Neither formulation was associated with any serious adverse events.

Conclusion: In this study in healthy male subjects, the 2 sibutramine formulations were pharmacokinetically equivalent, and the newly developed formulation had a safety profile comparable to that of the conventional formulation.