Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity

Author:

Zimmerman Kanecia O.12,Wu Huali2,Maharaj Anil3,Turner Alex4,Chen Jia-Yuh5,Hornik Chi D.12,Arnold Susan6,Muller William7,Al-Uzri Amira8,Meyer Marisa9,Shiloh-Malawsky Yael10,Taravath Sasidharan11,Lakhotia Arpita12,Joshi Charuta13,Jackman Jennifer2,Hornik Christoph P.12

Affiliation:

1. Department of Pediatrics (KOZ, CDH, CPH), Duke University Medical Center, Durham, NC

2. Duke Clinical Research Institute (KOZ, HW, CDH, JJ, CPH), Duke University, Durham, NC

3. Pharmaceutical Sciences (AM), The University of British Columbia, Vancouver, British Columbia, Canada

4. Undergraduate Student (AT), North Carolina State University, Raleigh, NC

5. Senior Biostatistician (JYC), The EMMES Corporation, Rockville, MD

6. Department of Neurology and Neurotherapeutics (SA), University of Texas Southwestern Medical Center Dallas, Dallas, TX

7. Infectious Disease (WM), Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL

8. Pediatric Nephrology (AA-U), Oregon Health and Science University, Portland, OR

9. Pediatric Critical Care (MM), Nemours Children’s Health, Wilmington, DE

10. Department of Neurology (YS-M), University of North Carolina at Chapel Hill, Chapel Hill, NC

11. Pediatric Neurology (ST), Coastal Children’s Services, Wilmington, NC

12. Pediatric Neurology (AL), Norton Children’s Hospital and University of Louisville, Louisville, KY

13. Pediatric Neurology (CJ), The Children’s Hospital Colorado, Aurora, CO

Abstract

OBJECTIVE Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49–10.44] and 3.71 [0.86–13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Publisher

Pediatric Pharmacy Advocacy Group

Subject

Pharmacology (medical),Pediatrics, Perinatology and Child Health

Reference34 articles.

1. Fryar CD CM , AffulJ. Prevalence of overweight, obesity, and severe obesity among children and adolescents aged 2–19 years: United States, 1963–1965 through 2017–2018. National Center for Health Statistics (NCHS) Health E-Stats. Published 2020. Updated January 29, 2021. Accessed April 21, 2022. https://www.cdc.gov/nchs/data/hestat/obesity-child-17-18/obesity-child.htm#Suggested%20citation

2. Dosing dilemmas in obese children;Mulla;Arch Dis Child Educ Pract Ed,2010

3. Pharmacokinetics and drug dosing in obese children;Kendrick;J Pediatr Pharmacol Ther,2010

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