Institute for Clinical Pharmacodynamics, 43 British American Blvd., Latham, NY, 12110, USA,
Clin Pharmacokinet. 2013 Oct;52(10):907-17. doi: 10.1007/s40262-013-0081-6.
Hydrocodone is a semi-synthetic narcotic analgesic and antitussive. Although hydrocodone products have been on the market for over 50 years, relatively little is known about its pharmacokinetics. Additionally, there are no published reports of population pharmacokinetic analyses for hydrocodone. Furthermore, current labeling of hydrocodone-containing products provides little guidance in terms of the impact of patient descriptors on the pharmacokinetics of hydrocodone. The objectives of this analysis were to develop a population pharmacokinetic model that characterizes the pharmacokinetics of hydrocodone following single and multiple oral doses of hydrocodone extended-release capsules (hydrocodone bitartrate ER capsules) in healthy subjects and patients, to examine the impact of patient descriptors on pharmacokinetic parameters and to assess the dose-proportionality of hydrocodone pharmacokinetic.
A total of 4,714 plasma hydrocodone concentrations from 220 subjects were available for this analysis. The data were extracted from seven studies (five phase 1 and two phase 2 studies). A two-compartment open mamillary model with linear elimination and a complex absorption model was used to fit the data, using NONMEM(®) version 7.1.2 software. The absorption model involved two sequential first-order absorption processes with the delay in the first process accomplished by means of multiple transit compartments. Covariate analysis was performed using standard forward selection followed by backward elimination processes. Model evaluation was performed using a prediction-corrected visual predictive check (pcVPC).
The population estimates of apparent oral central volume of distribution and apparent oral linear clearance were 714 L and 64.4 L/h, respectively. The first absorption process was rapid. Creatinine clearance and body surface area (BSA) were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. The pcVPC indicated that the model provided a robust and unbiased fit to the data.
A linear model for hydrocodone elimination provided an adequate fit to the observed data over the entire dose range, which supports that hydrocodone bitartrate ER capsules exhibit dose-proportional pharmacokinetics. The formulation of hydrocodone bitartrate ER capsules results in absorption profiles that are variable across and within subjects. Despite the variability in absorption profiles, a relatively simple model provided an adequate fit to the data. Creatinine clearance and BSA were statistically significant predictors of the apparent oral clearance and apparent oral volume of distribution. Absorption characteristics of hydrocodone bitartrate ER capsules should still allow effective plasma concentrations of hydrocodone to be reached quickly and for effective concentrations to be maintained for a long period.
氢可酮是一种半合成的麻醉性和镇咳性镇痛药。尽管氢可酮产品已经上市超过 50 年，但对其药代动力学的了解相对较少。此外，目前尚无关于氢可酮群体药代动力学分析的报道。此外，目前含有氢可酮的产品的标签几乎没有提供关于患者特征对氢可酮药代动力学影响的指导。本分析的目的是建立一个群体药代动力学模型，以描述健康受试者和患者单次和多次口服氢可酮缓释胶囊（酒石酸氢可酮 ER 胶囊）后氢可酮的药代动力学特征，考察患者特征对药代动力学参数的影响，并评估氢可酮药代动力学的剂量比例性。
共有 220 名受试者的 4714 份血浆氢可酮浓度数据可用于本分析。这些数据是从七项研究（五项 I 期和两项 II 期研究）中提取出来的。使用 NONMEM（®）版本 7.1.2 软件，采用具有线性消除的两室开放式乳突模型和复杂吸收模型来拟合数据。吸收模型涉及两个连续的一级吸收过程，第一个过程的延迟通过多个转运隔室来实现。协变量分析采用标准的正向选择和反向消除过程进行。使用预测校正的可视化预测检查（pcVPC）进行模型评估。
群体估计的表观口服中央分布容积和表观口服线性清除率分别为 714 L 和 64.4 L/h。第一吸收过程很快。肌酐清除率和体表面积（BSA）是表观口服清除率和表观口服分布容积的统计学显著预测因子。pcVPC 表明，该模型对数据的拟合具有稳健性和无偏性。
氢可酮消除的线性模型对整个剂量范围内的观察数据提供了足够的拟合，支持酒石酸氢可酮 ER 胶囊表现出剂量比例的药代动力学。酒石酸氢可酮 ER 胶囊的配方导致吸收谱在个体之间和个体内具有可变性。尽管吸收谱存在变异性，但相对简单的模型对数据提供了足够的拟合。肌酐清除率和 BSA 是表观口服清除率和表观口服分布容积的统计学显著预测因子。酒石酸氢可酮 ER 胶囊的吸收特征仍应允许迅速达到有效的血浆氢可酮浓度，并维持较长时间的有效浓度。
