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Application of Physiologically Based Pharmacokinetic Modeling to Characterize the Effects of Age and Obesity on the Disposition of Levetiracetam in the Pediatric Population

  • 期刊论文

  • 发表日期：

    2024年5月30日

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  • Patricia D. Maglalang,
  • Jaydeep Sinha,
  • Kanecia Zimmerman,
  • Sean McCann,
  • Andrea Edginton,
  • Christoph P. Hornik,
  • Chi D. Hornik,
  • William J. Muller,
  • Amira Al-Uzri,
  • Marisa Meyer,
  • Jia-Yuh Chen,
  • Ravinder Anand,
  • Eliana M. Perrin,
  • 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,
  • Susan Abdel-Rahman,
  • Elizabeth Payne,
  • Lily Chen,
  • Gina Simone,
  • Kathleen O’Connor,
  • Jennifer Cermak,
  • Lawrence Taylor,
  • Ramany John,
  • William Muller,
  • Ram Yogev,
  • Laura Fearn,
  • Sasidharan Taravath,
  • Tiffony Blanks,
  • Arielle Lapid,
  • Chi Hornik,
  • Melissa Harward,
  • Kira Clark,
  • Sarah Craven,
  • Kimberly Grzesek,
  • Charuta Joshi,
  • Austin Drake,
  • Lauri Filar,
  • Jennifer Sargent,
  • Arpita Lakhotia,
  • 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,
  • Martha Blackford,
  • Michael Reed,
  • Amanda Hodge,
  • Tasha Capozzi,
  • Heather Anthony,
  • Glenn Stryjewski,
  • Kimberly Klipner,
  • Karen Kowal,
  • Benjamin Traisman,
  • Carol Nielsen,
  • Pam Sroka,
  • Matitiahu Berkovitch,
  • Elkana Kohn,
  • Catherine Litalien,
  • Julie Autmizguine,
  • Diane Desmarasis,
  • Christine Massicotte,
  • Mariana Dumitrascu,
  • Vincent Lague,
  • Neil Goldenberg,
  • Peter Mourani,
  • Jendar Deschenes,
  • Domninic DiDomenico,
  • Megan Dix,
  • Gentle Halstenson,
  • Kathryn Malone,
  • Kimberly Ralston,
  • Alleluiah Rutebemberwa,
  • Yamila Sierra,
  • Matthew Steinbeiss,
  • Kevin Van,
  • Hugh McMillan,
  • Roger Zemek,
  • Thierry Lacaze,
  • Daniela Pohl,
  • Angie Tuttle,
  • Barbara Murchison,
  • Sara Ieradi,
  • Stuart Goldstein,
  • Gary Bradley,
  • Stuart Goldstein,
  • Theresa Mottes,
  • Tara Terrell,
  • Patricia Arnold,
  • Bradley DePaoli,
  • Bradley Gerhardt,
  • Cassie Kirby,
  • Kevin Watt,
  • Grace Jefferson,
  • Nicole Baisden,
  • Heidi Tiedge,
  • Christie Milleson,
  • Samantha Wrenn,
  • Anne Baez,
  • Scott Denne,
  • Brenda Poindexter,
  • Gregory Sokol,
  • Brianne Kost,
  • Ashley Moore,
  • Jaime Deville,
  • Kavita Shankar,
  • Elizabeth Lang,
  • Yaron Finkelstein,
  • Maggie Rumantir,
  • Mobeen Rathore,
  • Kathleen Thoma,
  • Alexandrea Borges,
  • Philip Toltzis,
  • David Speicher,
  • Eloise Lemon,
  • Brenna Vitou,
  • Eileen Goldblatt,
  • Ramon Adams,
  • Catherine Tasi,
  • Lisa Petersen,
  • Ashlee Parsons,
  • 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,
  • Michael Spigarelli,
  • Catherine Sherwin,
  • Fumiko Alger,
  • JoAnn Narus,
  • Rebbecca Perez,
  • Priscilla Rosen,
  • Yakub Salman,
  • Kaylynn Shakespear,
  • Joshua Shimizu,
  • Sharada Dixit,
  • Paula Delmore

摘要

Background

Levetiracetam is an antiseizure medication used for several seizure types in adults and children aged 1 month and older; however, due to a lack of data, pharmacokinetic (PK) variability of levetiracetam is not adequately characterized in certain populations, particularly neonates, children younger than 2 years of age, and children older than 2 years of age with obesity.

Objective

This study aimed to address the gap by leveraging PK data from two prospective standard-of-care pediatric trials (n = 88) covering an age range from 1 month to 19 years, including those with obesity (64%), and applying a physiologically based PK (PBPK) modeling framework.

Methods

A published PBPK model of levetiracetam for children aged 2 years and older was extended to pediatric patients younger than 2 years of age and patients older than 2 years of age with obesity by accounting for the obesity and age-related changes in PK using PK-Sim® software. The prospective pediatric data, along with the literature data for neonates and children younger than 2 years of age, were used to evaluate the extended PBPK models.

Results

Overall, 82.4% of data fell within the 90% interval of model-predicted concentrations, with an average fold error within twofold of the accepted criteria. PBPK modeling revealed that children with obesity had lower weight-normalized clearances (0.053 L/h/kg) on average than children without obesity (0.063 L/h/kg). The effect of maturation was well-characterized, resulting in comparable PBPK-simulated, weight-normalized clearances for neonates and children younger than 2 years of age reported from the literature.

Conclusions

PBPK modeling simulations revealed that the current US FDA-labeled pediatric dosing regimen listed in the prescribing information can produce the required exposure of levetiracetam in these target populations with dose adjustments for children with obesity aged 4 years to younger than 16 years.