Maglalang Patricia D, Wen Jiali, Hornik Christoph P, Gonzalez Daniel
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Duke Clinical Research Institute, Durham, North Carolina, USA.
Clin Transl Sci. 2024 Apr;17(4):e13793. doi: 10.1111/cts.13793.
Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.
癫痫患儿有多种治疗选择，包括手术、饮食疗法、神经刺激和抗癫痫药物（ASMs）。抗癫痫药物是一线治疗方法，有30多种抗癫痫药物已获得美国食品药品监督管理局（FDA）批准，用于治疗儿童各种癫痫和发作类型。鉴于FDA对儿童抗癫痫药物的广泛批准，考虑儿童期生理和发育变化如何影响药物处置至关重要。不同外在和内在因素（如患者体型、年龄、药物相互作用和药物剂型）导致的各种药代动力学（PK）变异性来源，可能会导致抗癫痫药物给药剂量欠佳。由于伦理和实际原因，在新生儿、婴儿和儿童中开展临床药理学研究存在障碍，限制了获得充分表征这些药物处置情况并更好阐明药代动力学变异性来源的可用数据。建模和模拟提供了规避传统和密集临床药理学方法的途径，以解决儿童癫痫和发作管理方面的差距。本综述讨论了影响儿童抗癫痫药物药代动力学和药效学（PD）变异性的各种生理和发育变化，并将详细讨论几种关键的抗癫痫药物。我们还将回顾针对年幼儿童群体的新型试验设计，强调癫痫疗效外推的作用，以及使用基于生理的药代动力学建模作为研究儿童药代动力学/药效学变异性来源的工具。最后，我们将总结当前在优化这些药物在儿童各年龄段的疗效和安全性方面面临的挑战以及未来的方向。
