A Model-Based Pharmacokinetic Comparison of Delayed-Release/Extended-Release Methylphenidate to Extended-Release Methylphenidates with Immediate-Release Supplementation

Abstract: Purpose: Immediate-release methylphenidate (IR MPH) is sometimes dosed in the afternoon to extend the duration of effect of a morning-dosed extended-release (ER) MPH for attention-deficit/hyperactivity disorder (ADHD). We compared pharmacokinetic (PK) models of DR/ER-MPH (formerly HLD200), an evening-dosed delayed-release and extended-release methylphenidate released in the colon that has no immediate-release component, to simulations of morning-dosed ER MPH with afternoon IR MPH supplementation. Methods: Established population PK models were used to simulate regimens comprising an ER MPH (54-mg osmotic release oral system MPH, 60-mg MPH controlled-release delivery, 60-mg MPH ER oral suspension, 20-mg ER dexmethylphenidate, or 60-mg multilayer-release MPH) administered in the morning with a 5- or 10-mg IR MPH given 8 hours post-ER dose. These simulations were compared to the PK model for evening-dosed 100-mg DR/ER-MPH monotherapy (given 10 hours prior to the ER MPH). Results: All simulations of afternoon IR MPH supplementation increased total exposure (AUC) and increased either the peak concentration (Cmax) or the number of local maxima compared to ER MPH alone. Compared to afternoon-supplemented simulations, the modeled PK profile of DR/ER-MPH exhibited a similar AUC with a lower Cmax. Conclusions: PK modeling of DR/ER-MPH compared to ER MPH + IR MPH regimens corroborates two clinical trials that demonstrated a duration of effect with DR/ER-MPH that lasts the entire waking day without the need for IR supplementation. Moreover, increasing the dose of DR/ER-MPH can achieve similar or higher afternoon/evening MPH exposure compared to afternoon-supplemented regimens without the effects of additional MPH peaks and troughs or increasing Cmax.Short Description: DR/ER-MPH is an evening-dosed delayed-release and extended-release methylphenidate that is released in the colon; it has no immediate-release component and provides a dose-dependent duration of effect for individuals with attention-deficit/hyperactivity disorder (ADHD). This study compared a population pharmacokinetic model of DR/ER-MPH to models of morning-dosed extended-release methylphenidates supplemented with afternoon-dosed immediate-release methylphenidate. The DR/ER-MPH model demonstrated similar or higher methylphenidate exposure versus the afternoon-supplemented regimens without the effects of increased peak concentration or additional peaks/troughs.Name of Sponsoring Organization(s): Ironshore Pharmaceuticals & Development, Inc., manufacturer of DR/ER-MPH (formerly HLD200)