College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si, Jeollanam-do, 57922, Republic of Korea.
College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.
Daru. 2024 Dec;32(2):631-648. doi: 10.1007/s40199-024-00533-y. Epub 2024 Aug 15.
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.
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.
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.
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.
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.
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.
洛索洛芬已被广泛用于缓解肌肉骨骼疼痛和炎症症状。然而，目前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较少。
本研究旨在通过群体药代动力学（Pop-PK）建模方法，确定与洛索洛芬个体内 PK 变异性相关的有效协变量，为建立科学的给药方案提供依据。
本研究以 52 名健康韩国男性的洛索洛芬生物等效性 PK 结果和个体的生理生化参数为基础数据，建立洛索洛芬的 Pop-PK 模型。为了根据洛索洛芬暴露情况同时预测活性形式的 PK，还使用了洛索洛芬的活性代谢物反式-醇洛索洛芬的先前 PK 结果来扩展模型。
洛索洛芬的 Pop-PK 特征可通过非顺序双吸收和 2 处置隔室的基本结构来描述，对于个体内 PK 变异性，外周隔室分布容积可与体表面积（BSA）相关，中央隔室清除率可与肌酐清除率（CrCL）和白蛋白水平相关。通过模型模拟，洛索洛芬及其醇代谢物在血浆中的浓度随着 CrCL 和白蛋白水平的升高而显著降低，反之亦然。此外，结果还证实，BSA 越高，洛索洛芬向外周的分布越多，稳态时洛索洛芬和醇代谢物在血浆中的最小浓度增加约 1.78-2 倍，而最大和最小浓度之间的波动减少。这些结果表明，BSA 较大、肾功能受损和血清白蛋白水平较高的患者可能会显著增加洛索洛芬和反式-醇洛索洛芬的血浆暴露。这也表明，由于长期应用洛索洛芬，该患者群体可能会导致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增加。
本研究通过发现有效协变量并建立能够解释人群中洛索洛芬 PK 多样性的定量模型，为洛索洛芬的科学精准医学方法提供了非常有用的起点。
本研究中使用的临床研究方案经过韩国光州全南国立大学生物等效性和桥接研究机构的机构审查委员会的彻底审查和批准。生物等效性研究许可编号如下：041113；10.15.2004。
