School of Pharmacy, Husson University, Bangor, ME 04401, USA.
Department of General Surgery, University of Michigan Medical School, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
Eur J Pharm Sci. 2018 Jan 1;111:465-481. doi: 10.1016/j.ejps.2017.10.009. Epub 2017 Oct 10.
Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (C) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.
丙戊酸（VPA）是一种较早的一线抗癫痫药物，具有复杂的药代动力学（PK）特征，目前正在研究其在几种新的神经和非神经适应症中的应用。我们的研究目的是设计和验证一种成人和儿童 VPA 处置的机制模型；并评估其对药物相互作用（DDI）的预测性能。本研究通过纳入 UGT 酶动力学和用于延长释放（ER）制剂的先进溶解、吸收和代谢（ADAM）模型，扩展了现有的基于生理学的药代动力学（PBPK）模型。VPA IR 和 ER 制剂的 PBPK 模型使用 Simcyp Simulator（版本 15）构建。对于即刻释放（IR）制剂和 ADAM 模型，使用一级吸收，对于 ER 制剂，使用包括控释特征的 ADAM 模型。使用来自 21 项已发表临床研究的数据来评估模型性能。该模型准确预测了从 200mg 到 1000mg 的单剂量和稳态剂量的 IR 制剂的浓度-时间曲线。同样，也模拟了单剂量和稳态剂量分别为 500mg 和 1000mg 时 ER 制剂的曲线。此外，模拟的 PK 曲线与在接受 VPA ER 制剂的儿科患者和接受 VPA IR 制剂的肝硬化成年患者的研究中观察到的数据吻合良好。该模型还通过包含 8 个队列的 I 期临床试验中成年个体数据进行了进一步验证，该个体数据在静脉输注 VPA 后，剂量范围从 15 至 150mg/kg。使用该模型模拟了 VPA 作为酶抑制剂与受药药物苯妥英或劳拉西泮，以及作为酶诱导剂卡马西平和苯巴比妥的底物的共同给药，以评估药物相互作用。模拟的血清浓度-时间曲线在第 5 和第 95 个百分位数内，大多数预测的 AUC 和峰血浆浓度（C）值在报告的平均值的 25%内。本研究定义的综合 VPA PBPK 模型可用于支持剂量方案优化，以改善该药物在不同情况下的安全性和疗效。
