Abstract
To determine if a literature-sourced physiological model for immediate-release (IR) methylphenidate (MPH), with addition of parameters for extended-release (ER) absorption can be adapted for NONMEM analysis to describe extended-release MPH drug products (i.e., Concerta® ER 54 mg tablets and Ritalin-LA® 40 mg capsules) pharmacokinetics (PK) in adults. This semi-physiological model will provide a platform to allow more accurate determination of Cmax in the analysis of methylphenidate plasma data from formulations with complex absorption. Adult reference data for total MPH plasma levels (summation of d- and l- enantiomers) were generated using individual subject parameters from a published NONMEM model for ER MPH (individual subject parameter generated data was used because the true experimental data is proprietary with only the previously-published summary parameters available for public use). The IR physiological model required analysis of both d- and l-MPH enantiomers which were estimated at each time point for the data by calculating the d/l enantiomer ratio from total MPH plasma concentration levels, based upon literature ratio estimates. Absorption was characterized by a fast zero-order and a delayed slow first-order release. Consistent with the literature IR model, two duplicate physiological models were used to describe the d- and l-MPH enantiomers. The mean and variability ratios for the individual subject parameter-generated data/true experimental data were very close to 1.0. The predictive performance of the absorption-modified physiological model and its disposition parameters were demonstrated, as they described both the Concerta® and Ritalin LA® PK and Cmax values very well. The bias was less than 6% for Concerta® peaks while peak 1 for d-Ritalin LA® was 12.9% and peak 2, 7.5%. The IR MPH physiological model, adapted for NONMEM analyses of the ER MPH drug products Concerta® and Ritalin LA® described the individual parameter-generated reference data well for both formulations.
Highlights
A clear relationship has been established between MPH blood plasma concentration levels, their time course and clinical effect in treating Attention Deficit Hyperactivity Disorder (ADHD), attention deficit hyperactivity disorder [1]
Results indicated that other than at 24 hr., the per cent bias for the mean total concentrations as a function of time was less than 10% for Concerta® and Ritalin LA® and most ratios for the standard deviation and standard error were near 1
Because the data differences observed were relatively minor, this study demonstrates the utility of the ER semi-physiological model developed here
Summary
A clear relationship has been established between MPH blood plasma concentration levels, their time course and clinical effect in treating ADHD, attention deficit hyperactivity disorder [1]. There is no plasma interconversion with all clinical efficacy being related the d-isomer concentrations [2] This relationship is reflected in the labeled recommended bid, twice-a-day, and tid, three-times-a-day, dosing for the original IR MPH drug products. A recent paper described a deterministic physiological IR model for oral and iv, intravenous, MPH dosing in several species, including humans, for d- and l- MPH [2]. This model was recently modified by the authors to describe the PK behavior of multiple ER MPH drug products in adults [5]. The ER characteristics were described by a complex transit model
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