A randomized phase I study to evaluate the safety, tolerability, pharmacokinetics and food-effect of Iguratimod in healthy adult volunteers

The aim of this study was to investigate the safety, maximum tolerated dose and pharmacokinetics (PK) of iguratimod and the effect of food on PK parameters in healthy adult volunteers. This phase 1 study consisted of four parts. Part 1 was a single-ascending dose (3.125, 6.25, 12.5, 25, 50, 75 mg) study to assess the maximum tolerated dose and safety of iguratimod. Part 2 was a single-ascending dose study to analyze the pharmacokinetic (PK) parameters of iguratimod; subjects were divided into three groups, with each group receiving iguratimod at a different dose (25, 50 or 75 mg). Part 3 was designed to compare the pharmacokinetic parameters of iguratimod between single-dose and multiple-dose administration; subjects were divided into two groups, with one group receiving a single dose of 50 mg on day 1 and the other group receiving a multiple dose of 50 mg, once every day, until a stable plasma concentration had been achieved. The aim of part 4 was to evaluate the effect of food on the pharmacokinetic parameters of iguratimod; subjects were divided into two groups, namely a fed group and a fasted group, with each group receiving a single 50 mg dose of iguratimod on day 1. Following a 14-day washout period, the two groups were crossed-over and received a single dose of 50 mg iguratimod on day 15. In part 1 of the study, iguratimod at doses ranging from 3.125 to 50 mg were well tolerated, with most adverse effects (AEs) being mild; no severe AEs occurred. In part 2, there were no significant differences in T-max, T-1/2, K-a and V/F among volunteers receiving doses of 25, 50 and 75 mg iguratimod. The C-max and AUC(0-last) in volunteers receiving 75 mg iguratimod were higher than those in volunteers receiving 25 and 50 mg. The C-max was linear from 25 to 75 mg, with a correlation coefficient (r (2)) of 0.9808. The AUC(0-last) was also linear from 25 to 75 mg, with an r (2) of 0.9839. In part 3, in subjects receiving multiple doses of 50 mg, the T-1/2 was 10.25 h, T-max was 3.63 h, C-max was 1.88 mg/L, AUC(0-last) was 31.88 mg/L h, V-d was 1.16 L and K-a was 0.87 1/h.There were no significant differences in the C-max, AUC(0-last), K-a and V/F between the single-dose and multiple-dose groups; there were, however, significant differences in T-max and T-1/2 between the two groups. In part 4, there were no significant differences in T-1/2, AUC(0-last), K-a and V/F between the fed group and fasted group; however, food may promote the absorption of iguratimod. The maximum tolerated dose for iguratimod was confirmed to be 50 mg. The ingestion of food was able to increase the peak concentration of iguratimod and shorten the time to peak concentration. Therefore, based on our results, iguratimod can be administered with food. The PK profile and metabolic effects of iguratimod support further clinical development for its application in treating autoimmune diseases.