Physiologically-based pharmacokinetic modeling of oxcarbazepine and levetiracetam during adjunctive antiepileptic therapy in children and adolescents.
Physiologically-based pharmacokinetic modeling of oxcarbazepine and levetiracetam during adjunctive antiepileptic therapy in children and adolescents.
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在儿童和青少年的辅助性抗癫痫治疗期间，基于生理的Oxcarbazepine和Levetiracetam的药代动力学建模。
DOI：
10.1002/psp4.12750
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Gonzalez D
中科院分区：
文献类型：
--
作者：
Sinha J;Karatza E;Gonzalez D
奥卡西平 (OXZ) 和左乙拉西坦 (LEV) 是两种新一代抗癫痫药物，通常与酶诱导抗癫痫药物 (EIAED) 联合用于儿童。 OXZ 和 LEV 的抗癫痫作用分别与 OXZ 活性代谢物 10-单羟基衍生物 (MHD) 和（母体）LEV 的暴露有关。然而，关于年龄和 EIAED 对 MHD 和 LEV 药代动力学 (PK) 的混杂影响知之甚少。为了解决这一知识差距，我们使用 2 岁以上儿童的文献数据在 PK-Sim 软件中进行了基于生理学的药代动力学 (PBPK) 建模。在存在（第 1 组）和不存在（第 2 组）伴随 EIAED 的情况下，对 MHD 和 LEV 清除率 (CL) 的年龄相关变化进行了表征。 EIAED 的药物相互作用效应根据第 1 组和第 2 组之间 CL 估计值的差异进行估计。PBPK 模型表明，年幼儿童的体重标准化 CL (ml/min/kg) 高于年长儿童（即，由于年龄的影响）。伴随的 EIAED 进一步将任何年龄的 MHD 的 CL 增加至 25% 的固定程度，但 EIAED 对 LEV CL 的影响随着年龄的增长而增加，从 20%（2 岁时）增加到 30%（青春期）。使用最大推荐剂量 (MRD) 的模拟显示，未接受 EIAED 的 2 至 4 岁以及 4 岁以上儿童分别面临超过 OXZ 和 LEV 参考暴露范围的风险。该分析证明了使用 PBPK 模型来理解年龄和药物治疗对儿童和青少年 PK 的混杂影响。
Oxcarbazepine (OXZ) and levetiracetam (LEV) are two new generation anti‐epileptic drugs, often co‐administered in children with enzyme‐inducing antiepileptic drugs (EIAEDs). The anti‐epileptic effect of OXZ and LEV are linked to the exposure of OXZ’s active metabolite 10‐monohydroxy derivative (MHD) and (the parent) LEV, respectively. However, little is known about the confounding effect of age and EIAEDs on the pharmacokinetics (PKs) of MHD and LEV. To address this knowledge gap, physiologically‐based pharmacokinetic (PBPK) modeling was performed in the PK‐Sim software using literature data from children greater than or equal to 2 years of age. Age‐related changes in clearance (CL) of MHD and LEV were characterized, both in the presence (group 1) and absence (group 2) of concomitant EIAEDs. The drug‐drug interaction effect of EIAEDs was estimated as the difference in CL estimates between groups 1 and 2. PBPK modeling suggests that bodyweight normalized CL (ml/min/kg) is higher in younger children than their older counterparts (i.e., due to an influence of age). Concomitant EIAEDs further increase MHD’s CL to a fixed extent of 25% at any age, but EIAEDs’ effect on LEV’s CL increases with age from 20% (at 2 years) to 30% (at adolescence). Simulations with the maximum recommended doses (MRDs) revealed that children between 2 and 4 years and greater than 4 years, who are not on EIAEDs, are at risk of exceeding the reference exposure range for OXZ and LEV, respectively. This analysis demonstrates the use of PBPK modeling in understanding the confounding effect of age and comedications on PKs in children and adolescents.
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影响因子：
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