Drug‐Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects

• Published in: Clinical pharmacology in drug development 2022-11, Vol.11 (11), p.1253-1263
• Main Authors: Chen, Jin, Stringer, Rowan, Shah, Bharti, Gu, Jessie, Zhang, Yiming, Hackling, Melissa, Prince, William, Woessner, Ralph
• Format: Article
• Language: English
• Subjects: Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - pharmacology; cytochrome P450; Drug Interactions; drug‐drug interactions; Healthy Volunteers; Humans; Itraconazole; nonalcoholic steatohepatitis; Pharmacokinetics; Rifampin; tropifexor; uridine 5′‐diphosphoglucuronosyltransferases
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.1140

Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5′‐diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug‐drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration–time curve [AUC] from time 0 to the last quantifiable concentration [AUClast] and AUC from time 0 to infinity [AUCinf] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug‐drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.