OBJECTIVE: The d-isomer of methylphenidate (d-MPH) is the pharmacologically active part of the racemic mixture of methylphenidate (d,l-MPH), which has been used for decades in the treatment of attention-deficit/hyperactivity disorder (ADHD). A modified release formulation with bimodal release for the pure d-enantiomer (Focalin XR) has been developed to enable a fast onset of action and a sustained activity for once-daily administration. It was intended to achieve a bimodal concentration-time profile as observed after administration of two immediate release Focalin tablets. The pharmacokinetics of this d-MPH bimodal release formulation were compared with a d-MPH immediate release formulation and a similar bimodal release formulation of d,l-MPH in healthy adult volunteers. MATERIALS AND METHODS: 25 volunteers received a single 20 mg dose of d-MPH bimodal release formulation, two 10 mg doses of a d-MPH immediate release formulation given 4 h apart and a single 40 mg dose of d,l-MPH bimodal release formulation (1 : 1 ratio for d : l enantiomers). The washout between treatments in this 3-way crossover study was 7 days. RESULTS: All three formulations were well-tolerated at the doses tested. The d-MPH bimodal release formulation generated two distinct d-MPH plasma concentration peaks and both peak concentrations and the time to peak were similar to those of the d-MPH immediate release formulation given 4 h apart and the d,l-MPH bimodal release formulation. The three formulations had Cmax and AUC0-infinity values of 15.5 +/- 4.3 ng/ml and 119 +/- 41 ng x h/ml for bimodal release d-MPH, 17.9 +/- 5.3 ng/ml and 115 +/- 40 ng A h/ml for immediate release d-MPH, and 16.4 +/- 4.4 ng/ml and 122 +/- 36 ng x h/ml for d,l-MPH bimodal release, respectively. CONCLUSIONS: In summary, the 20 mg extended (bimodal) release formulation of d-MPH (Focalin XR) demonstrated a bimodal concentration-time profile and was bioequivalent to two 10 mg doses of immediate release d-MPH (Focalin) and was bioequivalent to 40 mg extended (bimodal) release d,l-MPH (Ritalin LA).