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Steady-State Bioavailability of Extended-Release Methylphenidate (MPH-MLR) Capsule vs. Immediate-Release Methylphenidate Tablets in Healthy Adult Volunteers

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Abstract

Objectives

The objective of the study was to determine the relative bioavailability of an extended-release multilayer bead formulation of methylphenidate hydrochloride (MPH-MLR) 80 mg vs. methylphenidate immediate-release (IR; Ritalin®) tablets as single and multiple doses in the fed state.

Methods

A single-center, multiple-dose, randomized, open-label, two-period crossover study conducted in 26 healthy adults assigned to 4 days of once-daily MPH-MLR 80 mg or IR methylphenidate 25 mg three times daily.

Results

MPH-MLR 80 mg 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 ~7 h post dose. Maximum concentration was lower for MPH-MLR 80 mg than IR methylphenidate 25 mg three times daily on day 1 (23.70 vs. 31.47 ng/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 4 h (74.5 ± 15.2 ng·h/mL) was greater than IR methylphenidate 25 mg three times daily (66.0 ± 17.4 ng·h/mL), confirming steady-state levels during the study period. All treatment regimens were safe and well tolerated.

Conclusion

MPH-MLR 80-mg capsule once daily or IR methylphenidate 25 mg three times daily provides comparable maximum methylphenidate concentrations and systemic exposure in the fed state.

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Notes

  1. Rhodes Pharmaceuticals L.P. has received conditional acceptance from the US Food and Drug Administration to use the name Aptensio XR™ for this extended-release methylphenidate product.

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Acknowledgments

Dr. Adjei is Executive Director of Product Development at Rhodes Pharmaceuticals L.P. and was Study Director for this study. This study was conducted at Frontage Laboratories, Exton, PA, USA. The authors acknowledge the contribution of Lisa Diamond, PhD, for her contribution to the conduct of this study. Medical writing support was provided by Linda Wagner and Malcolm Darkes, medical writers at Excel Scientific Solutions, and funded by Rhodes Pharmaceuticals L.P.

Conflicts of interest

Dr. Adjei is the Executive Director of Product Development at Rhodes Pharmaceuticals L.P. and was study director for this study. Dr. Kupper is an employee of Rhodes Pharmaceuticals L.P. Dr. Teuscher is a consultant for Rhodes Pharmaceuticals L.P. Dr. Wigal is an advisor board member/consultant/speakers bureau member for Eli Lilly, Ironshore, Neos, NextWave, Noven, NuTec, Pfizer, Purdue, Rhodes Pharmaceuticals L.P., Shionogi, Shire, and Tris and has received grant and research support from Eli Lilly, Forest Laboratories, the National Institutes of Health, NextWave, Noven, NuTec, Rhodes Pharmaceuticals L.P., Shire, and Sunovion. Dr. Sallee is advisory board member/consultant/speakers bureau member for Ironshore, Neos, NextWave, Impax Labs, Otsuka Pharmaceutical Development and Commercialization, Purdue, Rhodes Pharmaceuticals L.P., Shionogi, and Shire, and has received grant and research support from the National Institutes of Health, Rhodes Pharmaceuticals L.P., and Shire. Dr. Sallee has an equity interest in and is member board of directors for P2D Bioscience Inc. Dr. Childress is an advisory board member/consultant/speakers bureau member for Bristol-Myers Squibb, Ironshore, NextWave, Novartis, Pfizer, Shionogi, and Shire, and has received research support from Arbor, Bristol-Myers Squibb, Forest Research Institute, Johnson & Johnson Pharmaceutical Research & Development, Lilly USA, Neos, Neurovance, NextWave, Novartis, Noven, Otsuka, Pfizer, Rhodes Pharmaceuticals L.P., Sepracor, Shionogi, Shire, Sunovion, Theravance, and Tris. Dr. Kollins has received research support and/or consulting fees from the following sources: Akili Interactive, Alcobra, Arbor, Atentiv, the Environmental Protection Agency, the National Institutes of Health (National Institute on Drug Abuse, National Institute of Environmental Health Sciences), Neos, Otsuka, Pfizer, Purdue, Rhodes Pharmaceuticals L.P., Shire, and Tris. Dr. Greenhill has received research support from the National Institutes of Health (National Institute on Drug Abuse) and Shire and is on the advisory board for BioBehavioral Diagnostics.

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Authors and Affiliations

  1. Rhodes Pharmaceuticals L.P., 498 Washington St, Coventry, RI, 02816, USA

    Akwete Adjei & Robert J. Kupper

  2. PK/PD Associates, 5 Hale Court, Trophy Club, TX, 76262, USA

    Nathan S. Teuscher

  3. AVIDA Inc., 1600 Dove Street, Suite 305, Newport Beach, CA, 92660, USA

    Sharon Wigal

  4. Department of Psychiatry, University of Cincinnati, 260 Stetson Street, Suite 3200, Cincinnati, OH, 45219, USA

    Floyd Sallee

  5. Center for Psychiatry and Behavioral Medicine, Inc., 7351 Prairie Falcon Rd, Suite 160, Las Vegas, NV, 89128, USA

    Ann Childress

  6. Duke University, 2608 Erwin Road, Suite 300, Durham, NC, 27705, USA

    Scott H. Kollins

  7. Columbia University and New York State Psychiatric Institute, 1051 Riverside Drive, Room 231A, Kolb Annex, New York, NY, 10032, USA

    Laurence Greenhill

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  1. Akwete Adjei
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  2. Robert J. Kupper
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Correspondence to Akwete Adjei.

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Adjei, A., Kupper, R.J., Teuscher, N.S. et al. Steady-State Bioavailability of Extended-Release Methylphenidate (MPH-MLR) Capsule vs. Immediate-Release Methylphenidate Tablets in Healthy Adult Volunteers. Clin Drug Investig 34, 795–805 (2014). https://doi.org/10.1007/s40261-014-0234-x

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  • DOI: https://doi.org/10.1007/s40261-014-0234-x

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