Hong Taegon, Han Seunghoon, Lee Jongtae, Jeon Sangil, Yim Dong-Seok
Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine.
Department of Clinical Pharmacology and Therapeutics, Seoul St Mary's Hospital; PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea.
Drug Des Devel Ther. 2016 Dec 7;10:3995-4003. doi: 10.2147/DDDT.S123318. eCollection 2016.
Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high-fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull-type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data.
普瑞巴林是一种抗惊厥药物，用于治疗成人神经性疼痛和部分性癫痫发作。本研究的目的是建立一个群体药代动力学（PK）模型，以描述普瑞巴林在空腹或餐后的吸收特征。使用了五项健康受试者单剂量或多剂量（150毫克）普瑞巴林PK研究（n = 88）的数据。普瑞巴林每日给药两次，早晨不进餐或餐后30分钟（常规饮食或高脂饮食）给药，晚上餐后30分钟或4小时（常规饮食）给药。在最后一剂后长达24小时收集系列血浆样本进行PK分析。由于传统的一级吸收模型无法正确模拟峰浓度，因此使用非线性混合效应方法（NONMEM；版本7.3）在二室线性PK模型上测试了埃尔朗频率分布、韦布尔型吸收和转运室模型。无论进餐状态如何，转运室模型最能描述普瑞巴林的吸收特征。我们得出结论，应根据模型开发和验证的原则仔细选择吸收模型，而不是因其流行和简单而遵循传统的一级吸收模型，尤其是当PK数据集包含密集采样的吸收相数据时。
