OBJECTIVE Metformin is an effective treatment for type 2 diabetes mellitus. The pharmacokinetic characteristics of the conventional immediate-release (IR) formulation of metformin (Glucophage), however, necessitate two- or three-times-daily dosing. Development of a novel extended-release (XR) formulation of metformin (Glucophage XR) using GelShield Diffusion System technology provides a once-daily dosing option. The objective of this study was to assess the steady-state pharmacokinetics of metformin XR tablets. METHODS This was an open-label, multiple-dose, five-regimen, two-sequence clinical study lasting 5 weeks. METHODS Subjects were 16 healthy volunteers aged 18-40 years. Three 1-week regimens of metformin XR (500, 1000 and 1500 mg once daily) were administered sequentially. Subjects were alternately given either metformin XR 2000 mg once daily or metformin IR 1000 mg twice daily during weeks 4 and 5. The pharmacokinetic properties of metformin XR were assessed on two separate days at steady state and compared with those of metformin IR. RESULTS Absorption of metformin XR was slower than that of metformin IR (time to maximum plasma concentration = 7 versus 3 hours). Maximum plasma concentrations (Cmax) following the administration of metformin XR 2000 mg once daily was 36% higher than that following the evening dose of metformin IR 1000 mg twice daily. The extent of absorption, determined by area under the plasma concentration-time curve (AUC), was equivalent for both formulations. The mean accumulation ratio of metformin XR was 1.0, indicating no accumulation with multiple-dose administration. Intrasubject variabilities in Cmax and AUC of metformin were comparable between metformin XR and metformin IR. This novel formulation of metformin XR was well tolerated at single doses up to 2000 mg once daily for 7 days, and adverse events were similar to those reported with metformin IR. CONCLUSIONS The pharmacokinetic parameters of metformin XR tablet using GelShield Diffusion System technology were similar to those of metformin IR. Metformin XR was well tolerated at single doses up to 2000 mg once daily.