Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment
Background/Objectives: 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 t...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/16/12/1540 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846103188325793792 |
|---|---|
| author | Mohammed S. Alasmari Faleh Alqahtani Fawaz Alasmari Abdullah Alsultan |
| author_facet | Mohammed S. Alasmari Faleh Alqahtani Fawaz Alasmari Abdullah Alsultan |
| author_sort | Mohammed S. Alasmari |
| collection | DOAJ |
| description | Background/Objectives: 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. |
| format | Article |
| id | doaj-art-29f5466c1d6547d9978aa5a6d48280c0 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-29f5466c1d6547d9978aa5a6d48280c02024-12-27T14:46:26ZengMDPI AGPharmaceutics1999-49232024-12-011612154010.3390/pharmaceutics16121540Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic ImpairmentMohammed S. Alasmari0Faleh Alqahtani1Fawaz Alasmari2Abdullah Alsultan3Drug and Poisoning Information Center, Security Forces Hospital, Riyadh 11481, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaBackground/Objectives: 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.https://www.mdpi.com/1999-4923/16/12/1540PBPKetrasimodliver impairmentprecision dosing |
| spellingShingle | Mohammed S. Alasmari Faleh Alqahtani Fawaz Alasmari Abdullah Alsultan Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment Pharmaceutics PBPK etrasimod liver impairment precision dosing |
| title | Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment |
| title_full | Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment |
| title_fullStr | Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment |
| title_full_unstemmed | Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment |
| title_short | Model-Based Dose Selection of a Sphingosine-1-Phosphate Modulator, Etrasimod, in Patients with Various Degrees of Hepatic Impairment |
| title_sort | model based dose selection of a sphingosine 1 phosphate modulator etrasimod in patients with various degrees of hepatic impairment |
| topic | PBPK etrasimod liver impairment precision dosing |
| url | https://www.mdpi.com/1999-4923/16/12/1540 |
| work_keys_str_mv | AT mohammedsalasmari modelbaseddoseselectionofasphingosine1phosphatemodulatoretrasimodinpatientswithvariousdegreesofhepaticimpairment AT falehalqahtani modelbaseddoseselectionofasphingosine1phosphatemodulatoretrasimodinpatientswithvariousdegreesofhepaticimpairment AT fawazalasmari modelbaseddoseselectionofasphingosine1phosphatemodulatoretrasimodinpatientswithvariousdegreesofhepaticimpairment AT abdullahalsultan modelbaseddoseselectionofasphingosine1phosphatemodulatoretrasimodinpatientswithvariousdegreesofhepaticimpairment |