3.3.2 Pharmacokinetics after continuous administration trial
The mean serum concentration–time data and PK parameters of EH were summarized shown in Table 4 and Figure 4. The mean serum concentration gradually increased with increasing dose, and the characteristics of serum concentration–time data in each dose group were similar. With the increase of the administered dose, the exposure of hirudin in the serum gradually increased and the trend of EH plasma concentration was similar to hirudin, basically showing a linear relationship. The hirudin in each dose group was below the lower limit of quantification after 28h of continuous administration, and the EH in each dose group was below the lower limit of quantification after 36h of continuous administration. The 0.45 mg/kg/h group had no significant accumulation after continuous administration, and the accumulation ratio AR_Cmax was less than 1.25. At the doses of 0.15mg/kg/h and 0.30mg/kg/h, the cumulative excretion rates of EH in urine from the start of administration to 48h after the end of administration were 4.6% and 9.9% respectively and the cumulative excretion rates of hirudin were 0.6% and 1.2%(Table 6). The total cumulative excretion rates of EH plus hirudin were 5.2% and 11.0% respectively, suggesting some other metabolites were produced from EH.