Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non-Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers.

Tropifexor (LJN452) is a potent, orally available, non-bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first-in-human study of tropifexor following single- and multiple-ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10- to 3000-µg tropifexor or placebo and 1 cohort receiving 300-µg tropifexor with a high-fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30-µg once-daily doses or placebo for 14 days. Pharmacodynamic assessment of fibroblast growth factor 19 and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose-proportional increases in exposure, and elimination half-life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ∼60%. With multiple dosing, steady state was reached on day 4 with <2-fold accumulation. Single and multiple doses showed dose-dependent increases in fibroblast growth factor 19. No changes in serum lipids were observed in tropifexor- vs placebo-treated obese subjects. In conclusion, tropifexor was well tolerated, had a pharmacokinetic profile suitable for once-daily dosing and showed dose-dependent target engagement without altering plasma lipids in healthy volunteers.

Pharmacokinetic and pharmacodynamic drug-drug interaction assessment between pradigastat and digoxin or warfarin.

Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, was evaluated for both pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions when co-administered with digoxin or warfarin in healthy subjects. This open-label study included two parallel subject cohorts each with three sequential treatment periods. Forty subjects were enrolled in the study with 20 subjects allocated to each cohort. PK and PD (PT/INR for warfarin only) samples were collected in each period. The statistical analysis results showed that the 90% CIs of the geometric mean ratios of digoxin, R-warfarin, and S-warfarin PK parameters (AUC and Cmax) were all within 0.80-1.25 interval. The 90% CIs of the geometric mean ratios of pradigastat PK parameters (AUC and Cmax) were within 0.80-1.25 interval when co-administered with warfarin; while co-administration with digoxin slightly reduced pradigastat exposure (∼15%). The results also showed that 90% CIs of the geometric mean ratios of warfarin PD parameters (AUC(PT), PTmax, AUC(INR), and INRmax) were within 0.80-1.25 interval. Pradigastat and digoxin or warfarin had no relevant clinical PK or PD drug-drug interactions. Administration of pradigastat and warfarin or pradigastat and digoxin as a mono or combined treatment appears to be safe and tolerated.