Details

Autor(en) / Beteiligte

• Maglalang, Patricia D.
• Sinha, Jaydeep
• Zimmerman, Kanecia
• McCann, Sean
• Edginton, Andrea
• Hornik, Christoph P.
• Hornik, Chi D.
• Muller, William J.
• Al-Uzri, Amira
• Meyer, Marisa
• Chen, Jia-Yuh
• Anand, Ravinder
• Perrin, Eliana M.
• Gonzalez, Daniel

Titel

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

Ist Teil von

• Clinical pharmacokinetics, 2024-06, Vol.63 (6), p.885-899

Ort / Verlag

Cham: Springer International Publishing

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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.