In Vitro and In Vivo Bioequivalence Study of 3D-Printed Instant-Dissolving Levetiracetam Tablets and Subsequent Personalized Dosing for Chinese Children Based on Physiological Pharmacokinetic Modeling

Abstract

Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups.

Predicting the correct dose in children: Role of computational Pediatric Physiological‐based pharmacokinetics modeling tools

“…The P‐PBPK dose prediction articles included in the study, the name of the drug, the platform, and the study's funding are described in Table 1. Verified PBPK models of drugs are presented in support of pediatric dose prediction (Figure 4): 13 articles reported results from P‐PBPK models, which are presented in support of dose selection, 30–42 five articles were on the optimization of dosage in the design of future pediatric clinical studies, 3,29,43–45 and six articles reported findings from studies on determining dose regimens 46–51 . Fourteen publications were on some special pediatric populations and uncommon diseases with an assessment of renal impairment, 52–56 children with obesity, 57–60 and pediatric patients with severe coronavirus disease 2019 (COVID‐19) disease 61–65 .…”

“…P‐PBPK models can be good predictors of gepotidacin dosing in a pediatric population. In 2021, Li et al 30 developed a combining BJ‐3DP and PBPK modeling approach to predict the drug‐time profile of 3D‐printed levetiracetam instant‐dissolving tablets (LEV‐IDTs) in children. That was the first time the PBPK model was used to estimate the dose of LEV in children instead of their body weight.…”