Fig 1.
Schematic depicting the physiological absorption model for immediate release (IR) and extended release (ER) MPH formulations.
The oral absorption model is composed of nine compartments, representing the stomach, duodenum, jejunum divided into two compartments, ileum divided into three compartments, cecum, and ascending colon. Dissolution of the IR component occurs throughout the GI tract, primarily in the stomach, whereas the release/dissolution of the ER component takes place only in the intestine accompanied by a delay time. M, metabolism; Loss, non-specific loss, IR immediate release.
Table 1.
Physiological model parameters for the gastrointestinal tract [31, 32].
Table 2.
Physiochemical and biochemical model parameters for IR and ER MPH.
Fig 2.
Model simulated versus observed d- MPH (A, B, C) and l-MPH (D, E, F) plasma concentration profiles in adults receiving a single oral dose of IR MPH at 0.3 μg/kg [17, 18] and 40 mg [19] under fasted conditions as well as model predictability of the pharmacokinetic parameters AUC (G) and Cmax (H).
Solid lines in A-F represent simulated mean plasma concentration-time profiles, whereas dashed lines represent the 5th and 95th percentiles for the predicted values. The observed data points (●) are shown as mean ± SD (error bars) or means only. The solid lines in G and H illustrate unity as well as a twofold deviation from unity; whereas the data points represent observed mean ± SD values with respective to the simulated mean ± SD values for AUC (G) and Cmax (H). In the study of Patrick, Straughn et al. (2007), AUC and Cmax values only reported for d-MPH.
Fig 3.
Model simulated versus observed total MPH plasma concentration profiles in adults receiving a single oral dose of MLR-MPH at (A) 20 mg [21] and (B) 80 mg [76] under fasting conditions, as well as model predictability of the pharmacokinetic parameters AUC (C) and Cmax (D).
Solid lines in A and B represent simulated mean plasma concentration-time profiles, whereas dashed lines represent the 5th and 95th percentiles for the predicted values. The observed data points (●) are shown as mean ± SD (error bars) for the study of Adjei et al (2014), while for Reiz et al. (2008), the observed data points are expressed as mean ± SE. The solid lines in C and D illustrates unity, as well as a twofold deviation from unity; whereas the data points represent observed mean ± SD values with respective to the simulated mean ± SD values for AUC (C) and Cmax (D).
Fig 4.
Model simulated versus observed total MPH plasma concentration profiles in adults receiving a single oral dose of Ritalin LA at (A, C) 40 mg [22, 23] and (B) 20 mg [9] under fasting conditions, as well as model predictability of the pharmacokinetic parameters AUC (D) and Cmax (E).
Solid lines in A-C represent simulated mean plasma concentration-time profiles, whereas dashed lines represent the 5th and 95th percentiles for the predicted values. The observed data points (●) are shown as mean ± SD or mean only. The solid lines in D and E illustrates unity, as well as a twofold deviation from unity; whereas the data points represent observed mean ± SD values with respective to the simulated mean ± SD values for AUC (D) and Cmax (E).
Fig 5.
Model simulated versus observed total MPH plasma concentration profiles in adults receiving a single oral dose of Metadate CD at 20 mg [24, 25] under fasting conditions (A and B), as well as model predictability of the pharmacokinetic parameters AUC (C) and Cmax (D).
Solid lines in A-B represent simulated mean plasma concentration-time profiles, whereas dashed lines represent the 5th and 95th percentiles for the predicted values. The observed data points (●) are shown as mean ± SD. The solid lines in C and D illustrates unity, as well as a twofold deviation from unity; whereas the data points represent observed mean ± SD values with respective to the simulated mean ± SD values for AUC (C) and Cmax (D).
Fig 6.
Model simulated versus observed total MPH plasma concentration profiles in adults receiving a single oral dose of Medikinet Retard at (A) 40 mg [23] and 20 mg [27, 28] (B and C) under fed conditions, as well as model predictability of the pharmacokinetic parameters AUC (D) and Cmax (E).
Solid lines in A-C represent simulated mean plasma concentration-time profiles, whereas dashed lines represent the 5th and 95th percentiles for the predicted values. The observed data points (●) are shown as mean except for Schutz et al (2009) where the observed data points are expressed as geometric mean. The solid lines in D and E illustrates unity, as well as a twofold deviation from unity; whereas the data points represent observed mean ± SD values (geometric mean ± SD values for the study of Schutz et al., 2009) with respective to the simulated mean ± SD values (geometric mean ± SD values for the study of Schutz et al., 2009) for AUC (D) and Cmax (E).
Fig 7.
Model parameters with absolute normalized sensitivity coefficient (NSC) values greater than 0.1 are listed in the Figure.
Table 3.
Fraction of ER component released and total MPH absorbed in each section.