Discussion
TEAEs, SAD
ADVERSE EVENTS, NERVOUS SYSTEM DISEASE, DELAYED GASTRIC EMPTYING
The present study reports the first phase I clinical trial of AD16. Preclinical studies of AD16 in rats demonstrated its good oral bioavailability and blood–brain barrier penetration with a large safety window.The linear dose analysis showed a The findings from trial studies administering multiple drug doses displayed that the trial drug doses were within the safety window and the effective dose could be maintained through the drug’s accumulation effect. Although the 40 mg dose exhibited higher exposure than 30 mg, the elimination and distribution characteristics were comparable in both groups. The efficacy and safety traits of these two dose groups could be further assessed in the follow-up therapeutic dose exploration test to support the therapeutic dose selection.The results indicated that a high-fat diet decreases the rate, but not the extent, of AD16 absorption. Food can affect drug absorption through delayed gastric emptying, changes in gastrointestinal pH, and biliary excretion [As for analyzing the excretion of AD16 metabolites in urine and feces, this study is the first clinical trial of AD16 tablets in humans, and the detection of metabolites is still being explored/implemented. Subsequent analysis will be supplemented according to the determined detection and analysis methods.In the SAD study, the adverse events with high incidence in AD16 group and placebo group involved various examinations and various nervous system disease, but the incidence was similar in both groups. In the MAD study, the safety profile of the AD16 group was comparable to that of the placebo group. In the FE study, the overall incidence of adverse events was similar after a high-fat diet and in fasting state. The incidence of adverse events in the MAD and FE studies was comparable to that in the SAD group. All TEAEs were grades I and II, mostly grade I, and were recovered or improved except for 7 subjects whose outcome was unknown due to loss of follow-up. No dose-related toxic reactions were observed in all studies, and no SAE occurred. Therefore, it is concluded that AD16 is generally a safe and well-tolerated drug. However, due to the limited sample size, subsequent trials are warranted to explore its safety further.There are some limitations in this study. Subjects were recruited from only one center in one country. The results might not represent the global and other regional populations. Second, because AD often requires long-term treatment, the results of the present study might not reflect the exact clinical scenario.