Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Janssen Research & Development, LLC, Spring House, PA, USA.
Clin Pharmacokinet. 2024 Oct;63(10):1435-1448. doi: 10.1007/s40262-024-01418-8. Epub 2024 Sep 19.
Valproic acid (VPA) demonstrates nonlinear pharmacokinetics (PK) due to a capacity-limited protein binding, which has potential implications on its total and unbound plasma concentrations, especially during hypoalbuminemia. A physiologically based pharmacokinetic (PBPK) model was developed to assess the nonlinear dose-exposure relationship of VPA with special emphasis on pediatric patients with hypoalbuminemia.
A PBPK model was first developed and evaluated in adults using PK-Sim and MoBi (v.11) and the scaled to children 1 year and older. The capacity-limited protein binding was characterized by second-order kinetics between VPA and albumin with a 2:1 molar ratio. All drug-specific parameters were informed by literature and optimized using published PK data of VPA. PK simulations were performed in virtual populations with normal and low albumin levels.
The reported concentration-time profiles of total and unbound VPA were adequately predicted by the PBPK model across the age and dose range (3-120 mg/kg). The model was able to characterize the nonlinear PK, as the concentration-dependent fraction unbound (f) and the related dose-dependent clearance values were well predicted. Simulated steady-state trough concentrations of total VPA were less than dose-proportional and were within the therapeutic drug monitoring range of 50-100 mg/L for doses between 30 and 45 mg/kg per day in children with normal albumin concentrations. However, virtual children with hypoalbuminemia largely failed to achieve the target exposure.
The PBPK model helped assess the nonlinear dose-exposure relationship of VPA and the impact of albumin concentrations on the achievement of target exposure.
丙戊酸（VPA）由于蛋白结合能力有限而呈现非线性药代动力学（PK），这对其总血浆浓度和游离血浆浓度有潜在影响，尤其是在低白蛋白血症时。建立了一种基于生理学的药代动力学（PBPK）模型，以评估 VPA 的非线性剂量-暴露关系，特别关注低白蛋白血症的儿科患者。
首先使用 PK-Sim 和 MoBi（v.11）在成人中开发和评估 PBPK 模型，并将其扩展到 1 岁及以上的儿童。VPA 与白蛋白之间的二级动力学特征为蛋白结合能力有限，摩尔比为 2:1。所有药物特异性参数均来自文献，并使用已发表的 VPA PK 数据进行优化。在具有正常和低白蛋白水平的虚拟人群中进行 PK 模拟。
报告的总 VPA 和游离 VPA 的浓度-时间曲线通过 PBPK 模型在整个年龄和剂量范围内（3-120mg/kg）得到了很好的预测。该模型能够描述非线性 PK，因为浓度依赖性游离分数（f）和相关的剂量依赖性清除值得到了很好的预测。在白蛋白浓度正常的儿童中，模拟的总 VPA 稳态谷浓度低于剂量比例，并且在 30-45mg/kg 每日剂量范围内，在 50-100mg/L 的治疗药物监测范围内。然而，具有低白蛋白血症的虚拟儿童在很大程度上未能达到目标暴露量。
PBPK 模型有助于评估 VPA 的非线性剂量-暴露关系以及白蛋白浓度对实现目标暴露的影响。
