Steady-state bioavailability of extended-release methylphenidate (MPH-MLR) capsule vs. immediate-release methylphenidate tablets in healthy adult volunteers.

Abstract

The objective of the study was to determine the relative bioavailability of an extended-release multilayer bead formulation of methylphenidate hydrochloride (MPH-MLR) 80mg vs. methylphenidate immediate-release (IR; Ritalin(®)) tablets as single and multiple doses in the fed state. A single-center, multiple-dose, randomized, open-label, two-period crossover study conducted in 26 healthy adults assigned to 4days of once-daily MPH-MLR 80mg or IR methylphenidate 25mg three times daily. MPH-MLR 80mg produced reproducible biphasic profiles of plasma methylphenidate concentrations characterized by a rapid initial peak, followed by a moderate decline reaching a plateau ~5 h post dose, then a gradual increase culminating in an attenuated second peak ~7h post dose. Maximum concentration was lower for MPH-MLR 80mg than IR methylphenidate 25mg three times daily on day 1 (23.70 vs. 31.47ng/mL); exposure was similar. The geometric mean ratios (MPH-MLR/IR methylphenidate [90% CI]) of log-transformed area under the plasma drug concentration-time curve to the last measurable observation (day 1: 0.88 [84.75-91.80]; day 4: 0.84 [81.16-86.94]), and area under the plasma drug concentration extrapolated to infinity (day 1: 0.93 [88.57-97.28]; day 4: 0.88 [84.48-91.17]) were within the 80-125% bioequivalence range. The mean±SD MPH-MLR 80-mg capsule day 4 area under the plasma drug concentration vs. time curve from 0 to 4h (74.5±15.2ng·h/mL) was greater than IR methylphenidate 25mg three times daily (66.0±17.4ng·h/mL), confirming steady-state levels during the study period. All treatment regimens were safe and well tolerated. MPH-MLR 80-mg capsule once daily or IR methylphenidate 25mg three times daily provides comparable maximum methylphenidate concentrations and systemic exposure in the fed state.