Alasmari Mohammed S, Alqahtani Faleh, Alasmari Fawaz, Alsultan Abdullah
Drug and Poisoning Information Center, Security Forces Hospital, Riyadh 11481, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Pharmaceutics. 2024 Dec 1;16(12):1540. doi: 10.3390/pharmaceutics16121540.
Etrasimod is a newly FDA-approved Sphingosine-1-Phosphate modulator indicated for moderate and severe ulcerative colitis. It is extensively metabolized in the liver via the cytochrome P450 system and may accumulate markedly in patients with hepatic dysfunction, exposing them to toxicity. The aim of the current study is to utilize a physiologically-based pharmacokinetic modeling approach to evaluate the impact of hepatic impairment on the pharmacokinetic behavior of etrasimod and to appropriately select dosage regimens for patients with chronic liver disease; Methods: PK-Sim was used to develop the etrasimod PBPK model, which was verified using clinical data from healthy subjects and subsequently adapted to reflect the physiological changes associated with varying degrees of hepatic dysfunction; Results: Simulations indicated that hepatic clearance of etrasimod is clearly reduced in patients with Child-Pugh B and C liver impairment. Based on these findings, dosing adjustments were proposed to achieve therapeutic exposures equivalent to those in individuals with normal liver function. In the Child-Pugh B and C population groups, 75% and 62.5%, respectively, of the standard dose were enough to have comparable exposure to the healthy population. These adjusted dosages aim to mitigate the risk of drug toxicity while maintaining efficacy; Conclusions: The PBPK model provides a robust framework for individualizing drug therapy in patients with hepatic impairment, ensuring safer and more effective treatment outcomes. Further clinical studies are warranted to verify these dosing recommendations and to refine the model for broader clinical applications.
埃特拉莫德是一种新获得美国食品药品监督管理局（FDA）批准的鞘氨醇-1-磷酸调节剂，适用于中度和重度溃疡性结肠炎。它通过细胞色素P450系统在肝脏中广泛代谢，在肝功能不全的患者中可能会显著蓄积，使他们面临毒性风险。本研究的目的是利用基于生理的药代动力学建模方法，评估肝损伤对埃特拉莫德药代动力学行为的影响，并为慢性肝病患者适当选择给药方案；方法：使用PK-Sim软件建立埃特拉莫德的生理药代动力学（PBPK）模型，该模型用健康受试者的临床数据进行验证，随后进行调整以反映与不同程度肝功能不全相关的生理变化；结果：模拟结果表明，Child-Pugh B级和C级肝损伤患者中埃特拉莫德的肝清除率明显降低。基于这些发现，提出了给药调整方案，以实现与肝功能正常个体相当的治疗暴露量。在Child-Pugh B级和C级人群组中，分别给予标准剂量的75%和62.5%就足以使暴露量与健康人群相当。这些调整后的剂量旨在降低药物毒性风险，同时保持疗效；结论：PBPK模型为肝损伤患者的个体化药物治疗提供了一个强大的框架，确保更安全、更有效的治疗结果。有必要进行进一步的临床研究来验证这些给药建议，并完善该模型以用于更广泛的临床应用。
