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Pharmacokinetics of Methylphenidate After Oral Administration of Two Modified-Release Formulations in Healthy Adults

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Abstract

Objective: To compare the rate and extent of absorption of DL-threo-methylphenidate (MPH) from two modified-release MPH formulations at their respective recommended starting doses in healthy adult volunteers.

Design: Open-label, randomised, crossover, bioavailability study.

Participants: Twenty healthy adult male and female volunteers.

Methods: Subjects received single doses of two modified-release formulations of MPH, a 20mg capsule (Ritalin® LA) and an 18mg tablet (Concerta®). A total of 19 plasma samples was collected over 24 hours, and MPH plasma concentrations were determined by liquid chromatography-mass spectrometry (LC-MS/MS). These values were used to calculate standard noncompartmental pharmacokinetic parameters describing the rate (peak concentration and time to peak concentration) and extent (area under the concentration-time curve, AUC) of absorption of the two formulations. The relative bioavailability of the two drugs was assessed using a 90% confidence interval, based on the lower and upper endpoints of the confidence interval for the ratios of the geometric means (log transformed) being within the 0.80–1.25 equivalence criterion.

Results: Nineteen subjects, ten male and nine female, aged 21–34 years completed both treatment phases of the study. The Ritalin® LA formulation displayed a distinctly biphasic pharmacokinetic profile, with mean initial peak plasma concentration of 7 µg/L at an average of 2.1 hours after administration and a second peak of 9.3 µg/L occurring at 5.6 hours. In contrast, the profile of the Concerta® formulation rapidly reached an initial plateau concentration of 3.4 µg/L at 3.3 hours after administration and a second mean plateau concentration of 5.9 µg/L approximately 6 hours after administration. Substantially more MPH was absorbed from Ritalin® LA than from Concerta® over the first 4 hours; the respective AUC4 values were 18.5 and 9.3 µg · h/L (p < 0.001). The overall extent of absorption of MPH was similar between the two formulations. Oral clearance was identical between the two dosage forms.

Conclusion: The Ritalin® LA formulation exhibited more rapid initial absorption and reached significantly higher peak plasma concentrations compared with the Concerta® formulation, although the oral bioavailability of MPH was similar between the two formulations. The Ritalin® LA capsule demonstrated a distinctly bimodal plasma concentration-time profile. MPH plasma concentrations resulting from Concerta® reached a peak at 6 hours. These results indicate that the recommended starting dose of the Ritalin® LA 20mg capsule formulation provides more rapid absorption and higher peak plasma concentrations than the recommended 18mg starting dose of the Concerta® formulation.

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Acknowledgments

This study was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The authors would like to acknowledge Dr Bernd Meibohm and Dr Ryan Yates for their assistance in the conduct of the clinical protocol. The authors further acknowledge the analytical assay development and support of Dr Fred Brill of National Medical Services, Willow Grove, PA, USA. The authors have provided no information on conflicts of interest directly relevant to the content of this study.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

    John S. Markowitz & Kennerly S. Patrick

  2. Department of Pharmaceutical Sciences, Drug Research Laboratory, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Arthur B. Straughn

  3. Department of Psychiatry and Behavioral Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

    C. Lindsay DeVane

  4. Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

    Linda Pestreich, James Lee, Yanfeng Wang & Rafael Muniz

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  1. John S. Markowitz
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Correspondence to John S. Markowitz.

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Markowitz, J.S., Straughn, A.B., Patrick, K.S. et al. Pharmacokinetics of Methylphenidate After Oral Administration of Two Modified-Release Formulations in Healthy Adults. Clin Pharmacokinet 42, 393–401 (2003). https://doi.org/10.2165/00003088-200342040-00007

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  • DOI: https://doi.org/10.2165/00003088-200342040-00007

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