Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates.
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 primate...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4153582?pdf=render |
| _version_ | 1819131032705695744 |
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| author | Xiaoxia Yang Suzanne M Morris Jeffery M Gearhart Christopher D Ruark Merle G Paule William Slikker Donald R Mattison Benedetto Vitiello Nathan C Twaddle Daniel R Doerge John F Young Jeffrey W Fisher |
| author_facet | Xiaoxia Yang Suzanne M Morris Jeffery M Gearhart Christopher D Ruark Merle G Paule William Slikker Donald R Mattison Benedetto Vitiello Nathan C Twaddle Daniel R Doerge John F Young Jeffrey W Fisher |
| author_sort | Xiaoxia Yang |
| collection | DOAJ |
| description | 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 in vitro 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. |
| first_indexed | 2024-12-22T09:09:04Z |
| format | Article |
| id | doaj.art-b5b645e24fba41e9a37210a41f624b02 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T09:09:04Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b5b645e24fba41e9a37210a41f624b022022-12-21T18:31:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10610110.1371/journal.pone.0106101Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates.Xiaoxia YangSuzanne M MorrisJeffery M GearhartChristopher D RuarkMerle G PauleWilliam SlikkerDonald R MattisonBenedetto VitielloNathan C TwaddleDaniel R DoergeJohn F YoungJeffrey W FisherThe 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 in vitro 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.http://europepmc.org/articles/PMC4153582?pdf=render |
| spellingShingle | Xiaoxia Yang Suzanne M Morris Jeffery M Gearhart Christopher D Ruark Merle G Paule William Slikker Donald R Mattison Benedetto Vitiello Nathan C Twaddle Daniel R Doerge John F Young Jeffrey W Fisher Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. PLoS ONE |
| title | Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. |
| title_full | Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. |
| title_fullStr | Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. |
| title_full_unstemmed | Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. |
| title_short | Development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates. |
| title_sort | development of a physiologically based model to describe the pharmacokinetics of methylphenidate in juvenile and adult humans and nonhuman primates |
| url | http://europepmc.org/articles/PMC4153582?pdf=render |
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