背景:洛索洛芬已在临床上积极用于缓解肌肉骨骼疼痛和炎症症状。然而,关于洛索洛芬在人群中的定量药代动力学(PK)预测工具和多样性分析的报道很少。
目的:本研究的目的是通过洛索洛芬的群体药代动力学(Pop-PK)建模方法,确定与解释个体间PK变异性相关的有效协变量,并为建立科学的给药方案提供起点。
方法:洛索洛芬对52名健康韩国男性进行的生物等效性PK结果以及来自每个个体的生理和生化参数被用作开发洛索洛芬Pop-PK模型的基础数据。为了根据洛索洛芬暴露同时预测活性形式的PKs,先前报道的反式醇洛索洛芬的PK结果,洛索洛芬的活性代谢产物,用于扩展模型。
结果:洛索洛芬的Pop-PK曲线是根据具有2位隔室的非顺序两次吸收的基本结构来描述的,对于个体间的PK变化,外周室体积的分布可能与体表面积(BSA)相关,和中央隔室清除率与肌酐清除率(CrCL)和白蛋白水平。作为模型模拟的结果,随着CrCL和白蛋白水平的升高和降低,血浆中洛索洛芬及其酒精代谢产物的浓度显着降低,分别。另一方面,证实BSA越高,洛索洛芬在外周的分布越大,血浆中洛索洛芬和酒精代谢物的最低浓度在稳态下增加了约1.78-2倍,而最大和最小浓度之间的波动减小。结果表明,患有大BSA的患者,肾功能受损,和高血清白蛋白水平可能显著增加血浆暴露于洛索洛芬和反式醇洛索洛芬。还表明,由于在该患者组中长期使用洛索洛芬,胃肠道系统和各种组织中的潜在副作用以及血浆中的暴露水平可以得到因果关系的解释。
结论:这项研究通过发现有效的协变量并建立定量模型来解释洛索洛芬PKs在人群中的多样性,从而为洛索洛芬的科学精准医学方法提供了非常有用的起点。
背景:本研究中使用的临床研究方案经过了生物等效性和桥接研究所机构审查委员会的全面审查和批准,Chonnam国立大学,光州,大韩民国。生物等效性研究许可证编号如下:041113;10.15.2004。
BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.
OBJECTIVE: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.
METHODS: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.
RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.
CONCLUSIONS: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.
BACKGROUND: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.