| Title: |
Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment |
| Authors: |
Chen, Jin; Gu, Jessie; Shah, Bharti; Stringer, Rowan; Reis da Silva Torrao, Leonel; Hackling, Melissa; Nidamarthy, Prasanna Kumar; Prince, William T.; Woessner, Ralph |
| Source: |
The Journal of Clinical Pharmacology ; volume 62, issue 4, page 520-531 ; ISSN 0091-2700 1552-4604 |
| Publisher Information: |
Wiley |
| Publication Year: |
2022 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Tropifexor, a non–bile acid farnesoid X receptor (FXR) agonist, has dose‐proportional pharmacokinetics and no obvious major enterohepatic circulation. This open‐label study investigated the effect of hepatic impairment (HI), as determined by Child‐Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200‐μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein‐binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6‐fold increase in unbound exposure (area under the plasma concentration–time curve from time 0 to infinity [AUC inf,u ]) and a 1.3‐fold increase in maximal exposure (C max,u ) vs those with normal hepatic function (geometric mean ratio: AUC inf,u , 1.64 [90%CI, 1.25‐2.16]; C max,u , 1.30 [90%CI, 0.96‐1.76]). Participants with severe HI (N = 8) had a 1.6‐fold increase in AUC inf,u (1.61 [90%CI, 1.04‐2.49]) and comparable C max,u (1.02 [90%CI, 0.60‐1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1002/jcph.1996 |
| Availability: |
https://doi.org/10.1002/jcph.1996; https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcph.1996; https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jcph.1996; https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/jcph.1996 |
| Rights: |
http://onlinelibrary.wiley.com/termsAndConditions#vor |
| Accession Number: |
edsbas.20439466 |
| Database: |
BASE |