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

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) IAI 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 I enrolled 20 healthy subjects to investigate the effect of the UGTIAI 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 (C-max) 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 [AUC(last)] and AUC from time 0 to infinity [AUC(inf)] reduced by only 10%), suggesting minor relevance of the UGTIAI pathway for clearance of tropifexor and no expected drug-drug interactions based on UGTIAI inhibition. Inhibition of CYP3A4 by itraconazole increased the C-max of tropifexor by only 9% and exposure (both AUC(last) and AUC(inf)) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased C-max (55%) and AUC (AUC(last) by 79% and AUC(inf) by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.

Automated summary

Tropifexor is a farnesoid X receptor agonist being developed for the treatment of nonalcoholic steatohepatitis. Drug-drug interaction studies showed that inhibition of UGTIA1 pathway has minor relevance for Tropifexor clearance, while CYP3A4 inhibition had a weak effect on Tropifexor PK. Inducing CYP3A4 with rifampin significantly decreased Tropifexor exposure. All coadministered drugs were well tolerated.