Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin(®)) in healthy adult volunteers

Abstract

Objectives: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin(®)) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths.

Methods: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours.

Results: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH.

Conclusions: MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR.

FIG.1.

Study design. Sequence 1: Multilayer extended-release bead methylphenidate (MPH-MLR) 80 mg capsule once daily (period 1); MPH-MLR 80 mg sprinkles once daily (period 2); and Ritalin^® 25 mg three times daily (period 3). Sequence 2: Ritalin 25 mg three times daily (period 1); MPH-MLR 80 mg capsule once daily (period 2); and MPH-MLR 80 mg sprinkles once daily (period 3). Sequence 3: MPH-MLR 80 mg sprinkles once daily (period 1); Ritalin 25 mg three times daily (period 2); and MPH-MLR 80 mg capsule once daily (period 3). PK, pharmacokinetic.

FIG.2.

(A) Mean plasma methylphenidate concentration-time profiles following single-dose administration of multilayer extended-release bead methylphenidate (MPH-MLR) 80 mg capsule, MPH-MLR 80 mg sprinkles, and Ritalin^® 25 mg three times daily under fasted conditions. Error bars represent standard deviation. (B) Individual plasma methylphenidate concentration-time profiles following single-dose administration of MPH-MLR 80 mg as intact capsule (fasted conditions). (C) Individual plasma methylphenidate concentration-time profiles following single-dose administration of MPH-MLR sprinkled on applesauce (fasted conditions). (D) Individual plasma methylphenidate concentration-time profiles following administration of Ritalin 25 mg three times daily (fasted conditions).

FIG.3.

Mean simulated concentration-time profiles for multilayer extended-release bead methylphenidate (MPH-MLR) dose strengths between 10 mg and 80 mg.