4.2 Pharmacokinetics
EH showed predictable pharmacokinetics after administered intravenously, with exposures increasing proportionally with dose. The pharmacokinetics parameters of EH in healthy volunteers were almost consistent with those found in preclinical study of monkeys and rats.
The concentration of EH in serum reached the peak within 5 minutes after the end of injection, with exposures (AUC and Cmax) increasing proportionally with doses between 0.2~2.0mg/kg in single-dose and 0.15~0.45mg/kg/h (24h) in continuous administration. After intravenous administration, the EH was mainly distributed in the extracellular fluid with an apparent distribution volume of 402.7-615.2 ml/kg, which was independent of the dosage.
Preclinical animal studies suggested that renal excretion was a major excretion route of EH, and the excretion in urine accounted for 65.9% of the total dose by isotope labeling of 131I. However, in this clinical study, the cumulative excretion rate in urine of prototype drugs plus hirudin only was less ten percent which indicated that EH produced other metabolites beside hirudin to excrete in urine. Indeed, excepting for EH and hirudin, the two major measurable metabolites in human urine after intravenous administration of EH we found that nine and ten metabolites were truncated at the C-terminal of EH and hirudin, respectively. This caused a successive reduction in amino acids at the C-terminus, which suggested the EH was metabolised to produce hirudin and other metabolites and that hirudin was metabolised to corresponding metabolites by the kidney17. These results suggested that metabolic pathway of EH in vivo was similar to that of hirudin.18 Moreover, the pharmacokinetic parameters and excretion of EH were also similar with hirudin.20
The pharmacokinetic parameters of hirudin and recombinant hirudin had been characterised in healthy volunteers.34 Native hirudin and recombinant hirudin undergo little, if any, hepatic metabolism. In the studies of hirudin, more than 70% of the drug was excreted unchanged in the urine within the first hour after intravenous administration, and 95% was eliminated after 5 hours.25 After a single intravenous injection in healthy volunteers, both native hirudin and recombinant hirudin have rapid distribution phases. The a half-life(T1/2) in studies with healthy volunteers ranged from 0.15 to 1.24 hours. The maximum plasma concentration (Cmax) was 0.6 to 1.0 mg/L. The volume of distribution (Vd) of native hirudin and recombinant hirudin ranged from 8.9 to 17.2L.34-36 These results suggested that EH was similar with hirudin in pharmacokinetic parameters.
The ratio of area under the curve of hirudin to EH was 4.0 ± 1.2%, indicating that a small amount of EH was cleaved into hirudin, resulting in the high safety and low bleeding potential of EH. In normal organisms, the levels of activated FXa and FXIa were low37 in that EH mainly existed in intact form, and its active metabolite was very low. However, the relationship between the activity level of hirudin and EH under in vivo hypercoagulable state was not clear, and further study was needed to establish the dose-effect relationship of EH in patients.
Interestingly, no hirudin was detected in the plasma samples of the 0.30 mg/kg/h group of continuous administration, while there was no significant difference in the concentration of EH between plasma and serum, which indicated that the hirudin in the serum may come from the process of blood coagulation in vitro accompanying the activated coagulate factors.
Considering the small sample size, the clinical therapeutic effect of EH should be confirmed by a future phase II–III study.