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

Authors: Markowitz J.S.¹; Straughn A.B.²; Patrick K.S.¹; DeVane C.L.³; Pestreich L.⁴; Lee J.⁴; Wang Y.⁴; Muniz R.⁴

Source: Clinical Pharmacokinetics, Volume 42, Number 4, 2003 , pp. 393-401(9)

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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

g/L at an average of 2.1 hours after administration and a second peak of 9.3

g/L occurring at 5.6 hours. In contrast, the profile of the Concerta^® formulation rapidly reached an initial plateau concentration of 3.4

g/L at 3.3 hours after administration and a second mean plateau concentration of 5.9

g/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

g • 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.

Conclusions: 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.

Keywords: Adrenoceptor agonists, pharmacokinetics; Methylphenidate, pharmacokinetics

Document Type: Research article

Affiliations: 1: 2 Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston,South Carolina, USA 2: 1 Department of Pharmaceutical Sciences, Drug Research Laboratory, University of Tennessee Health Science Center, Memphis, Tennessee, USA 3: 3 Department of Psychiatry and Behavioral Medicine, Medical University of South Carolina, Charleston, South Carolina, USA 4: 4 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA

Publication date: 2003-01-01

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

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