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

• Published in: Daru 2024-08, Vol.32 (2), p.631-648
• Main Authors: Jang, Ji-Hun, Kang, Ho-Suk, Jeong, Seung-Hyun
• Format: Article
• Language: English
• Subjects: Adult; Albumin; Analysis; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Bioequivalence; Biomedical and Life Sciences; Biomedicine; East Asian People; Gastrointestinal system; Healthy Volunteers; Humans; Male; Medical research; Medicinal Chemistry; Medicine, Experimental; Metabolites; Models, Biological; Pharmaceutical Sciences/Technology; Pharmacokinetics; Pharmacology/Toxicology; Phenylpropionates - administration & dosage; Phenylpropionates - blood; Phenylpropionates - pharmacokinetics; Physiological aspects; Plasma; Plasma physics; Republic of Korea; Research Article; Therapeutic Equivalency; Young Adult
• ISSN: 2008-2231; 1560-8115; 2008-2231
• DOI: 10.1007/s40199-024-00533-y

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 cova