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.