Development of a Physiologically Based Model to Describe the Pharmacokinetics of Methylphenidate in Juvenile and Adult Humans and Nonhuman Primates

<div><p>The widespread usage of methylphenidate (MPH) in the pediatric population has received considerable attention due to its potential effect on child development. For the first time a physiologically based pharmacokinetic (PBPK) model has been developed in juvenile and adult humans and nonhuman primates to quantitatively evaluate species- and age-dependent enantiomer specific pharmacokinetics of MPH and its primary metabolite ritalinic acid. The PBPK model was first calibrated in adult humans using <i>in vitro</i> enzyme kinetic data of MPH enantiomers, together with plasma and urine pharmacokinetic data with MPH in adult humans. Metabolism of MPH in the small intestine was assumed to account for the low oral bioavailability of MPH. Due to lack of information, model development for children and juvenile and adult nonhuman primates primarily relied on intra- and interspecies extrapolation using allometric scaling. The juvenile monkeys appear to metabolize MPH more rapidly than adult monkeys and humans, both adults and children. Model prediction performance is comparable between juvenile monkeys and children, with average root mean squared error values of 4.1 and 2.1, providing scientific basis for interspecies extrapolation of toxicity findings. Model estimated human equivalent doses in children that achieve similar internal dose metrics to those associated with pubertal delays in juvenile monkeys were found to be close to the therapeutic doses of MPH used in pediatric patients. This computational analysis suggests that continued pharmacovigilance assessment is prudent for the safe use of MPH.</p></div

Plasma concentrations obtained after oral dosing of children with MPH.

<p>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) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Shaywitz1" target="_blank">[47]</a>; 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) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Wigal1" target="_blank">[48]</a>; 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) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Quinn2" target="_blank">[51]</a>.</p

trouting

trouting vbl nWe children had some glorious adventures pursuing the great Newfoudland pastime, trouting. (We never did call it trout fishing, except when we wanted foreigners to know what we meant, for how could you expect aliens and strangers to know that trouting meant trout fishing?)PRINTED ITEM DNE-citG.M. Story APR 1974 JH APR 1974Used I and SupUsed I and SupUsed

Plasma concentrations obtained after oral dosing of boys with MPH.

<p>Panel A: Data represent model simulated (lines) and observed (circles) plasma concentrations of <i>d</i>-MPH (•) and <i>l</i>-MPH (○) after oral dosing with10 mg MPH in boys with ADHD (n = 9) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Srinivas2" target="_blank">[7]</a>; Panel B: Data as described for Panel A obtained after oral dosing with 10 mg MPH in boys with ADD (n = 5) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Srinivas4" target="_blank">[46]</a>. Thin lines depict model simulations with MPH-specific model parameters set to adult values, and thick lines represent model predictions of plasma <i>l</i>-MPH concentrations with the calibrated children oral model, for which the value of K5lC describing gut metabolism of <i>l</i>-MPH was decreased from the adult value of 1.426 to 0.1 1/h/kg^0.75, while other MPH-specific model parameters were set to adult values.</p

Plasma concentrations obtained after iv and oral dosing of adult monkeys with MPH (NCTR data).

<p>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) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Manjanatha1" target="_blank">[52]</a>; 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 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Manjanatha1" target="_blank">[52]</a>; 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/kg^0.75 to 1.05 and 35.65 1/h/kg^0.75 for <i>d</i>-MPH and <i>l</i>-MPH.</p

Plasma concentrations obtained after iv dosing of juvenile monkeys with MPH.

<p>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) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Wargin1" target="_blank">[24]</a>. 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 <i>d</i>-MPH and <i>l</i>-MPH were increased from adult values of 38,000 µg/h/kg^0.75, 90,000 µg/h/kg^0.75, 0.7 L/h/kg^0.75, and 0.7 L/h/kg^0.75 to 350,000 µg/h/kg^0.75, 700,000 µg/h/kg^0.75, 70 L/h/kg^0.75, and 70 L/h/kg^0.75, respectively.</p

Physiological model parameters.

a<p>male/female; ^bset to adult human values; ^efor both adult and juvenile monkeys; ^Hadult humans;^Cchildren; ^Mmonkeys.</p><p>Physiological model parameters.</p

Sensitive model parameters.

<p>Parameters with absolute NSC values greater than 1 are highlighted in bold.</p><p>Sensitive model parameters.</p

Metabolic pathways of methylphenidate in humans.

<p>Metabolic pathways of methylphenidate in humans.</p

Plasma concentrations and urinary excretion data obtained after iv dosing of healthy adult men with MPH.

<p>Panel A: data represent model simulated (lines) and observed (circles) plasma concentrations of <i>d-</i>MPH (•) and <i>l</i>-MPH (○) after iv dosing with 10 mg MPH (n = 13) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Srinivas1" target="_blank">[4]</a>; Panel B: data represent simulated (lines) and observed (triangles) urinary excretion of <i>d</i>-RA (▴) and <i>l</i>-RA (Δ) after iv dosing with 10 mg MPH (n = 9) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106101#pone.0106101-Srinivas3" target="_blank">[28]</a>. 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.</p