Population Pharmacokinetics of Loxoprofen and its alcoholic metabolites in healthy Korean men.

Autor:	Jang JH; 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., Kang HS; College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si, Jeollanam-do, 57922, Republic of Korea., Jeong SH; College of Pharmacy, Sunchon National University, 255 Jungang-ro, Suncheon-si, Jeollanam-do, 57922, Republic of Korea. jeongsh@scnu.ac.kr.; College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon-Si, 57922, Republic of Korea. jeongsh@scnu.ac.kr.
Jazyk:	angličtina
Zdroj:	Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences [Daru] 2024 Dec; Vol. 32 (2), pp. 631-648. Date of Electronic Publication: 2024 Aug 15.
DOI:	10.1007/s40199-024-00533-y
Abstrakt:	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. Objectives: 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. Method: 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. Conclusion: 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. Clinical Trial Registration: 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. Competing Interests: Declarations Ethical approval Clinical studies were conducted in accordance with the Rules of Good Clinical Practice and the revised Declaration of Helsinki for Biomedical Research with Human Subjects. All subjects had no prior history of hypersensitivity or related reactions to steroid drugs and were physically normal. In addition, healthy adults aged 19–55 years have no history of digestive, liver, kidney, cardiovascular, central nervous system, endocrine, or blood diseases in the past, and have not been taking any other drugs. All subjects underwent a physical examination, clinical screening, complete blood count, urinalysis, and blood chemistry analyzes prior to participation in this clinical study to confirm their physical health. Consent to participate All subjects provided written informed consent prior to their participation in bioequivalence and pharmacokinetic studies. Consent for publication All data were anonymized and participants were informed that the results of this study may be subject to publication and presentation in meetings. Conflicts of interest/ Competing interests The authors have no conflicts of interest relevant to this study to disclose. (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)
Databáze:	MEDLINE
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