Discussion
deaths, SAD
COMMON COLD, INFLUENZA
This Phase I trial assessed the safety, tolerability and PK characteristics of forsythin in healthy Chinese individuals. These findings indicate that single or multiple doses of forsythin (≤800 mg/day) are well tolerated in these individuals. No serious AEs or deaths were observed, and no AEs led to discontinuation of the study. The incidence or severity of all AEs was not correlated with the dose. The rates of AEs of forsythin were slightly lower than those of placebo in both the SAD and MAD studies. Forsythin did not show any safety risk compared to other drugs used to treat the common cold or influenza [The PK results of the SAD study confirmed that forsythin is rapidly absorbed. It has a short half-life for TID. Increasing the forsythin dose in subjects resulted in less than dose-proportional increases in exposures, indicative of exposure saturation. After a single dose, forsythin showed moderate variability in AUCAs concentrations for M1 were quite low due to the fast conjugation reaction, M1 was only analyzed in the 100 and 800 SAD cohorts. As trough concentrations are closely related to antipyretic function due to its mechanism, a doubling dose could be applied on the first dose to reach a steady state faster. Therefore, a doubling dose was applied in the 50 mg, and 100 mg MAD cohorts. Concentrations for forsythin 8 h post single dose were low (Steady-state for forsythin and metabolites was considered to have been reached by day 3 in the MAD study, which was consistent with In the food effect study, the absorption of forsythin was delayed and the Sulfotransferase (SULT) was previously reported to be the most active hepatic enzyme involved in the formation of M2. Compounds in the diet may inhibit the activities of SULT, thus decreasing the sulphation of forsythin [Further clinical trials are required to determine the efficacy of forsythin in patients. A phase 2 study of forsythin in patients infected with influenza is currently underway. Exposures of forsythin in 100–200 mg TID cohorts are higher than these for efficacy dose cohorts in animal models. Therefore, considering safety and efficacy, forsythin 200 mg TID for 5 days was chosen in the phase 2 study.Forsythin is safe and tolerable in healthy Chinese subjects. Forsythin is well-absorbed after single or multiple doses and is extensively metabolized. The sulphate conjugate M2 was the primary metabolite in the plasma. The preclinical pharmacodynamics, safety profile and PK characteristics of forsythin support further evaluations of its safety and efficacy in patients. Based on the data described above, 200 mg TID for five days was used for further clinical development.