Ogungbenro Kayode, Aarons Leon
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
Eur J Pharm Sci. 2014 Oct 15;63:45-52. doi: 10.1016/j.ejps.2014.06.023. Epub 2014 Jul 7.
Valproic acid is an anti-convulscant drug that is widely used in the treatment of different types of epilepsy and since its introduction the clinical use has increased rapidly both as a sole agent and in combination therapies. The mechanism of action has been linked to blockade of voltage-dependent sodium channels and potentiation of GABAergic transmission. The most widely used route of administration of Valproic acid is oral, although it can also be given intravenously and rectally and its pharmacokinetics has been studied extensively. The aim of this work was to develop a physiologically based pharmacokinetic model for plasma and tissue/organ prediction in children and adults following intravenous and oral dosing of Valproic acid. The plasma/tissue concentration profile will be used for clinical trial simulation in Dravet syndrome, a rare form of epilepsy in children where the combination of Valproic acid, stiripentol and clobazam has shown remarkable results. A physiologically based pharmacokinetic model was developed with compartments for gut lumen, enterocyte, gut tissue, systemic blood, kidney, liver, brain, spleen, muscle and rest of body. System and drug specific parameters for the model were obtained from the literature from in vitro and in vivo experiments. The model was initially developed for adults and scaled to children using age-dependent changes in anatomical and physiological parameters and ontogeny functions for enzyme maturation assuming the same elimination pathways in adults and children. The results from the model validation showed satisfactory prediction of plasma concentration both in terms of mean prediction and variability in children and adults following intravenous and oral dosing especially after single doses. The model also adequately predicts clearance in children. Due to limited distribution of Valproic acid into tissues, the concentration in plasma is about 8-9 times higher than tissues/organs. The model could help to improve clinical outcome in the treatment of Dravet syndrome through dose optimisation.
丙戊酸是一种抗惊厥药物，广泛用于治疗不同类型的癫痫。自引入以来，其临床应用作为单一药物或联合治疗均迅速增加。其作用机制与电压依赖性钠通道的阻断以及γ-氨基丁酸（GABA）能传递的增强有关。丙戊酸最常用的给药途径是口服，不过也可静脉注射和直肠给药，并且其药代动力学已得到广泛研究。这项工作的目的是建立一个基于生理学的药代动力学模型，用于预测儿童和成人静脉注射和口服丙戊酸后的血浆及组织/器官浓度。血浆/组织浓度曲线将用于模拟Dravet综合征的临床试验，Dravet综合征是儿童中一种罕见的癫痫形式，丙戊酸、司替戊醇和氯巴占联合使用已显示出显著效果。建立了一个基于生理学的药代动力学模型，包含肠腔、肠上皮细胞、肠组织、全身血液、肾脏、肝脏、大脑、脾脏、肌肉和身体其他部分等房室。该模型的系统和药物特定参数取自体外和体内实验的文献。该模型最初是为成人开发的，并根据解剖学和生理学参数随年龄的变化以及酶成熟的个体发育函数按比例缩小到儿童，假设成人和儿童的消除途径相同。模型验证结果表明，在静脉注射和口服给药后，尤其是单剂量给药后，模型对儿童和成人血浆浓度的预测在平均预测和变异性方面均令人满意。该模型也能充分预测儿童的清除率。由于丙戊酸在组织中的分布有限，血浆中的浓度比组织/器官高约8 - 9倍。该模型有助于通过优化剂量改善Dravet综合征的治疗临床结果。
