Figure 1.
Metabolic pathways of methylphenidate in humans.
Figure 2.
Schematic depicting the PBPK model for MPH and its primary metabolite RA.
Two identical 8-compartment models were constructed for d- and l-MPH and two identical one-compartment models were built for d- and l-RA. MPH was given intravenously or orally. In humans, MPH is metabolized predominantly by hydrolysis to pharmacologically inactive RA, which is subsequently excreted into urine.
Table 1.
Estimated tissue-plasma distribution coefficients for MPH.
Table 2.
Physiological model parameters.
Table 3.
Chemical specific model parameters.
Figure 3.
Plasma concentrations and urinary excretion data obtained after iv dosing of healthy adult men with MPH.
Panel A: data represent model simulated (lines) and observed (circles) plasma concentrations of d-MPH (•) and l-MPH (○) after iv dosing with 10 mg MPH (n = 13) [4]; Panel B: data represent simulated (lines) and observed (triangles) urinary excretion of d-RA (▴) and l-RA (Δ) after iv dosing with 10 mg MPH (n = 9) [28]. Observed data were digitalized from graphs and are expressed as mean or mean ± SD based on the ability to digitalize: this applies to all figure legends unless otherwise specified.
Figure 4.
Plasma concentrations obtained after oral dosing of healthy adults with MPH.
Panel A: data represent model simulated (lines) and observed (circles) plasma concentrations of d-MPH (•) and l-MPH (○) after oral dosing with 0.3 mg/kg MPH (n = 24) [29]; Panel B: Data as described for Panel A obtained after oral dosing with 0.3 mg/kg MPH (n = 19) [30]; Panel C: Data as described for Panel A obtained after oral dosing with 40 mg MPH (n = 21) [31].
Figure 5.
Plasma concentrations obtained after oral dosing of healthy adult men with MPH.
Panel A: data represent model simulated (lines) and observed plasma concentrations of MPH (•) and RA (▴) after oral dosing with 20 mg MPH (n = 5) [32]; Panel B: Data as described for Panel A obtained after oral dosing with 20 mg MPH (n = 8) [33]; Panel C: Data as described for Panel A obtained after oral dosing with 0.3 mg/kg MPH (n = 10) [24]; Panel D: Data as described for Panel A obtained after oral dosing with 0.15 mg/kg MPH (n = 5) [24].
Figure 6.
Plasma concentrations obtained after oral dosing of boys with MPH.
Panel A: Data represent model simulated (lines) and observed (circles) plasma concentrations of d-MPH (•) and l-MPH (○) after oral dosing with10 mg MPH in boys with ADHD (n = 9) [7]; Panel B: Data as described for Panel A obtained after oral dosing with 10 mg MPH in boys with ADD (n = 5) [46]. Thin lines depict model simulations with MPH-specific model parameters set to adult values, and thick lines represent model predictions of plasma l-MPH concentrations with the calibrated children oral model, for which the value of K5lC describing gut metabolism of l-MPH was decreased from the adult value of 1.426 to 0.1 1/h/kg0.75, while other MPH-specific model parameters were set to adult values.
Table 4.
Observed and simulated serum RA concentrations in boys after oral administration of MPH.
Figure 7.
Plasma concentrations obtained after iv and oral dosing of adult monkeys with MPH (NCTR data).
Panel A: Data represent model simulated (line) and observed (circles) individual plasma concentrations of MPH (•) after iv dosing with 0.3 mg/kg MPH (n = 4). One plasma sample at 6 h and two other plasma samples at 24 h contained non-quantifiable levels of MPH (0.1 µg/L limit of quantification, LOQ) [52]; Panel B: Data represent model simulated (line) and observed (triangles) individual plasma concentrations of RA (▴) after iv dosing with 0.3 mg/kg MPH (n = 4); Panel C: Data as described for Panel A obtained after oral dosing with 0.3 mg/kg MPH (n = 4). One plasma sample at 4 h and one plasma samples at 8 h contained non-quantitable levels of MPH [52]; Panel D: Data as described for Panel B obtained after oral dosing with 0.3 mg/kg MPH (n = 4). Dashed lines represent model predictions using kinetic model parameters derived from the adult human oral model, whereas solid lines depict model predictions using the calibrated adult monkey oral model, for which gut metabolism constants (K5dC and K5lC) were increased from adult human values of 0.042 and 1.426 1/h/kg0.75 to 1.05 and 35.65 1/h/kg0.75 for d-MPH and l-MPH.
Figure 8.
Plasma concentrations obtained after iv dosing of juvenile monkeys with MPH.
Data represent model simulated (thin lines for MPH and thick lines for RA) and observed plasma concentrations of MPH (•) and RA (▴) after iv dosing with 3 mg/kg MPH (n = 5) [24]. Dashed lines represent model simulations using hepatic metabolic constants derived from the adult monkey iv model, whereas solid lines depict model predictions using the calibrated juvenile monkey iv model, for which maximum metabolic constants (VmaxliverdC and VmaxliverlC) describing hepatic hydrolysis and clearance terms describing hepatic oxidation (KmetdC and KmetlC) for d-MPH and l-MPH were increased from adult values of 38,000 µg/h/kg0.75, 90,000 µg/h/kg0.75, 0.7 L/h/kg0.75, and 0.7 L/h/kg0.75 to 350,000 µg/h/kg0.75, 700,000 µg/h/kg0.75, 70 L/h/kg0.75, and 70 L/h/kg0.75, respectively.
Figure 9.
Plasma concentrations obtained after repeated oral dosing of juvenile male monkeys with MPH (NCTR data).
Panel A: Data denote representative model simulated (lines) and observed (circles) individual plasma concentrations of MPH (•) after repeated oral dosing with 2.5 mg/kg MPH (n = 1–4 at each time point); Panel B: Data depict representative model simulated (lines) and observed (circles) individual plasma concentrations of RA (•) after repeated oral dosing with 2.5 mg/kg MPH (n = 1–4 at each time point). Measurements of plasma RA concentrations at pre-dose (approximately within 30 min of dosing) were combined with those at 24 h from previous dose; Panel C: Data as described for Panel A obtained after oral dosing with 12.5 mg/kg MPH (n = 1–4 at each time point); Panel D: Data as described for Panel B obtained after oral dosing with 12.5 mg/kg MPH (n = 1–4 at each time point). MPH was administered twice a day, 4 h apart, five days a week (Monday to Friday) and kinetic studies were performed from Monday to Thursday. Kinetic profiles of MPH and RA for each individual monkey were followed on the same day of the week when quarterly blood sampling occurred over a 1 year period. On the day of blood collection, MPH was administered only once in the morning.
Figure 10.
Plasma concentrations obtained after oral dosing of healthy adult humans with MPH.
Panel A: Data represent model simulated (solid line, 90 mg MPH and dashed line, 50 mg MPH) and observed (circles) plasma concentrations of d-MPH after oral dosing with 90 mg (•) and 50 mg(○) MPH (n = 49) [34]; Panel B: Data represent model simulated (line) and observed (circles) plasma concentrations of d-MPH (•) after two repeated oral dosing with 30 mg/kg MPH, taken 6 h apart (n = 28) [35]; Panel C: Data represent model simulated (line) and observed (circles) plasma concentrations (○, test formulation; •, reference formulation) of MPH after oral dosing with 20 mg MPH (n = 20) [36]; Panel D: Data represent model simulated (line) and observed plasma concentrations of MPH (•) and RA (▴) after three repeated oral dosing with 5 mg/kg MPH, taken 4 h apart (n = 35) [37].
Figure 11.
Urinary excretion data obtained after oral dosing of healthy adult men with MPH.
Panel A: Data represent model simulated (line) and observed (circles) percentage of total dose excreted in urine as RA (•) after oral dosing with 20 mg MPH (n = 3) [20]; Panel B: Data represent model simulated (line) and observed (triangles) urinary excretion time courses of d-RA (▴) and l-RA (Δ) after oral dosing with 40 mg MPH (n = 9) [28].
Figure 12.
Plasma concentrations obtained after oral dosing of children with MPH.
Panel A: Data represent model simulated (lines) and observed (circles) plasma concentrations of d-MPH after oral dosing with 2.5 mg MPH in preschool-aged (•) (n = 1) and school-aged (○) (n = 2) children with ADHD [49]. Solid line represents simulations for preschool-aged children and dashed line represents simulations for school-aged children; Panel B: Data as described for Panel A obtained after oral dosing with 5 mg MPH in preschool-aged (•) (n = 8) and school-aged (○) (n = 2) children [49]; Panel C: Data as described for Panel A obtained after oral dosing with 7.5 mg MPH in preschool-aged (•) (n = 4) and school-aged (○) (n = 1) children [49]; Panel D: Data as described for Panel A obtained after oral dosing with 10 mg MPH in preschool-aged (•) (n = 1) and school-aged (○) (n = 4) children [49]; Panel E: Data represent model simulated (lines) and observed plasma concentration of d-MPH after oral dosing with 5 mg (×), 10 mg (○), and 20 mg (•) MPH in boys with ADHD (n = 31) [50].
Figure 13.
Plasma concentrations obtained after oral dosing of children with MPH.
Panel A: Data represent model simulated (dashed line, 0.6 mg/kg; solid line, 0.3 mg/kg) and observed (circles) plasma concentration of MPH after oral dosing with 0.6 mg/kg (○) and 0.3 mg/kg (•) MPH in boys with ADD (n = 14) [47]; Panel B: Data represent model simulated (line) and observed plasma concentrations (○, fasting, •, normal) of MPH normalized to a dose of 5 mg after three repeated oral dosing with 5–15 mg MPH, taken 4 h apart, in children with ADHD (n = 14) [48]; Panel C: Data represent model simulated individual (lines) and observed (circles) plasma concentrations of MPH (•) normalized to a dose of 20 mg after two repeated dosing with 10–40 mg MPH, taken 4 h apart, in children with ADHD (n = 14) [51].
Figure 14.
Plasma concentrations obtained after repeated oral dosing of juvenile monkeys with MPH.
Data represent model simulated (lines) and observed (circles) individual plasma concentrations of MPH at 10∶00 and 13∶00 after daily oral dosing with either 10.7 mg/kg (lower line) or 16.5 mg/kg (upper line) MPH at 9∶00 and 12∶00 (n = 8) [27].
Table 5.
Sensitive model parameters.