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Background <p>Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking.</p> Objective <p>This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension.</p> Methods <p>Two multicenter studies (NCT01431326 and NCT02993861) were conducted in patients receiving standard-of-care OXZ therapy. Participants ≥&#xa0;2 years of age with a body mass index ≥&#xa0;95th percentile were classified as obese. Plasma concentrations were measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. Nonlinear mixed effects modeling was performed using NONMEM 7.4 to characterize the population pharmacokinetics of OXZ and MHD simultaneously. Simulations were performed to compare MHD systemic exposure in children ≥&#xa0;2 years of age with and without obesity.</p> Results <p>One hundred study participants with a median (range) age of 9 years (44 days–20.90 years) contributed 425 plasma concentrations of OXZ (<i>n</i> = 212) and MHD (<i>n</i> = 213). Fifty-two percent of the participants had obesity. A one-compartment joint parent–metabolite model with linear input–output and bi-directional transformation between OXZ and MHD best characterized the pharmacokinetics. Body size was the only covariate affecting pharmacokinetics, and a fat-free mass–based metric termed pharmacokinetic weight&#xa0;(PKWT) best characterized that effect allometrically. Simulation results revealed that the current dosing regimen of OXZ can produce comparable exposure of MHD in children ≥&#xa0;2 years of age with and without obesity.</p> Conclusion <p>A model-informed analysis confirms that the current pediatric dosing regimen of OXZ applies to children in general, regardless of their obesity status.</p>

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Population Pharmacokinetic Modeling of Oxcarbazepine and Its Active Metabolite 10-Monohydroxy Derivative to Inform Dosing in Children with Obesity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Jaydeep Sinha,
  • Kanecia Zimmerman,
  • Stephen J. Balevic,
  • Chi Hornik,
  • William J. Muller,
  • Mobeen Rathore,
  • Marisa Meyer,
  • Yaron Finkelstein,
  • Amira Al-Uzri,
  • Arpita Lakhotia,
  • Stuart Goldstein,
  • Jia-Yuh Chen,
  • Ravinder Anand,
  • Daniel Gonzalez,
  • Daniel K. Benjamin Jr.,
  • Phyllis Kennel,
  • Cheryl Alderman,
  • Zoe Sund,
  • Kylie Opel,
  • Rose Beci,
  • Chi Dang Hornik,
  • Gregory L. Kearns,
  • Matthew Laughon,
  • Ian M. Paul,
  • Janice Sullivan,
  • Kelly Wade,
  • Paula Delmore,
  • Leanne West,
  • Elizabeth Payne,
  • Lily Chen,
  • Gina Simone,
  • Kathleen O’Connor,
  • Jennifer Cermak,
  • Lawrence Taylor,
  • Thomas Green,
  • Danny Benjamin,
  • Perdita Taylor-Zapata,
  • Kelly Wade,
  • Greg Kearns,
  • Ian Paul,
  • Julie Autmizguine,
  • Edmund Capparelli,
  • Rachel Greenberg,
  • Cheryl Alderman,
  • Terren Green,
  • Ramany John,
  • William Muller,
  • Ram Yogev,
  • Laura Fearn,
  • Sasidharan Taravath,
  • Tiffony Blanks,
  • Arielle Lapid,
  • Melissa Harward,
  • Nicole Baisden,
  • Kira Clark,
  • Sarah Craven,
  • Kimberly Grzesek,
  • Charuta Joshi,
  • Austin Drake,
  • Lauri Filar,
  • Jennifer Sargent,
  • Michael Oldham,
  • Julie Burmester,
  • Stephany Eubanks,
  • Terri Simeon,
  • Yael Shiloh-Malawsky,
  • Christopher Anderson,
  • Mallory Jolly,
  • Shradhdha Joshi,
  • Norbert Odero,
  • Jennifer Taylor,
  • Susan Arnold,
  • Caryn Harper,
  • Erica Howard,
  • Maria Martinez,
  • Deanna Myer,
  • Angela Walker,
  • Ton DeGrauw,
  • Macarthur Benoit,
  • Christopher Sims,
  • William Muller,
  • Ram Yogev,
  • Laura Fearn,
  • Benjamin Traisman,
  • Pam Sroka,
  • Carol Nielsen,
  • Kevin Watt,
  • Nicole Baisden,
  • Christie Milleson,
  • Samantha Wrenn,
  • Kathleen Thoma Saniyyah Mahmoudi,
  • Amna Riaz,
  • Alexandrea Borges,
  • Laura James,
  • Dawn Hansberry,
  • Michelle Hart,
  • Lee Howard,
  • D Pierce Ann,
  • Janice Sullivan,
  • Karrie Kernen,
  • Susan Poff,
  • Courtney Konow,
  • Kelli Brown,
  • Jen Comings,
  • Andrew Michael,
  • Jackie Perry,
  • Michelle Wiseheart,
  • Matthew Laughon,
  • Janice Bernhardt,
  • Ashley Mariconti,
  • Jennifer Talbert,
  • Glenn Stryjewski,
  • Ramany John,
  • Karen Kowal,
  • Kimberly Klipner,
  • Maggie Rumantir,
  • Gary Bradley,
  • Bradley Gerhardt,
  • Cassie Kirby,
  • Bradley DePaoli,
  • Patricia Arnold,
  • Tara Terrell,
  • Theresa Mottes,
  • Daniela Pohl,
  • Hugh McMilan,
  • Roger Zemek,
  • Thierry Lacaze,
  • Sara Leradi,
  • Angie Tuttle,
  • Barbara Murchison,
  • Kyle Patubo,
  • Connie Swanson,
  • Carrie Farrar,
  • Andrea Kuchler,
  • Jennifer Stubbs,
  • Kira Clark,
  • Sarah Craven,
  • Kimberly Grzesek,
  • Susan Lattimore,
  • Peter Mourani,
  • Neil Goldenberg,
  • Kevin Van,
  • Alleluiah Rutebemberwa,
  • Yamila Sierra,
  • Kathryn Malone,
  • Jendar Deschenes,
  • Matthew Steinbeiss,
  • Kimberly Ralston,
  • Gentle Hastenson,
  • Domninic DiDomenico,
  • Megan Dix,
  • Julie Autmizguine,
  • Catherine Litalien,
  • Vincent Lague,
  • Mariana Dumitrascu,
  • Diane Desmarasis,
  • Christine Massicotte

摘要

Background

Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking.

Objective

This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension.

Methods

Two multicenter studies (NCT01431326 and NCT02993861) were conducted in patients receiving standard-of-care OXZ therapy. Participants ≥ 2 years of age with a body mass index ≥ 95th percentile were classified as obese. Plasma concentrations were measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. Nonlinear mixed effects modeling was performed using NONMEM 7.4 to characterize the population pharmacokinetics of OXZ and MHD simultaneously. Simulations were performed to compare MHD systemic exposure in children ≥ 2 years of age with and without obesity.

Results

One hundred study participants with a median (range) age of 9 years (44 days–20.90 years) contributed 425 plasma concentrations of OXZ (n = 212) and MHD (n = 213). Fifty-two percent of the participants had obesity. A one-compartment joint parent–metabolite model with linear input–output and bi-directional transformation between OXZ and MHD best characterized the pharmacokinetics. Body size was the only covariate affecting pharmacokinetics, and a fat-free mass–based metric termed pharmacokinetic weight (PKWT) best characterized that effect allometrically. Simulation results revealed that the current dosing regimen of OXZ can produce comparable exposure of MHD in children ≥ 2 years of age with and without obesity.

Conclusion

A model-informed analysis confirms that the current pediatric dosing regimen of OXZ applies to children in general, regardless of their obesity status.