4.1 Safety
This trial was a first-in-human trial conducted in healthy volunteers to
explore the safety, tolerability, and pharmacokinetics of EH. The action
mechanism and structure determine that neorudin gestates the high safe
and low bleeding charaterestics which have already been proved in
preclinical studies. In this study, the safety and tolerance of EH was
also reconfirmed in healthy subjects within a single-dose of 0.2-2 mg/kg
and a continuous 24-hour administration of 0.15-0.45 mg/kg/h. Although
the level of hirudin in vivo increased with the increase of EH dose, the
level of hirudin was still very low, and almost no bleeding events
occurred. The adverse events were mostly reported in the clinical study
or application of hirudin, including the adverse reactions related to
bleeding and abnormal coagulation tests, such as hypohemoglobin and
reticulocyte count increase,23-25 and were soon
recovered after symptomatic treatment or without treatment. The
antithrombotic mechanism of EH was that the nitrogen EPR short peptide
of EH cleaved through FXIa and/or FXa, and the active metabolite hirudin
was released at the microthrombus site, which inhibited activity of
thrombin and the formation of new thrombus. Normally, EH had no
antithrombotic activity due of low FXIa, and antithrombotic activity
could only be produced when the coagulation system was
activated.17 This mechanism not only effectively
inhibited thrombosis, but also significantly reduced bleeding side
effects.
Activated partial thromboplastin time (APTT) was an important parameter
to measure the therapeutic effect of hirudin and to change the
therapeutic dose. Previous experiments had shown that
hirudin
significantly prolonged APTT, PT and TT, and the duration of APTT was
positively correlated with the plasma concentration of
hirudin.26,27 In
this study, the prolongation of APTT was only found in the single-dose
trial of 0.2mg group (1 case) and continuous administration of
0.30mg/kg/h (2 cases) and 0.45mg/kg/h (2 cases). The APTT increase of
the case in 0.2mg group was occurred on the 8th day after administration
when over 7 half-life elapsed, therefore it was not related to the study
drug. The prolongation of APTT in the continuous administration all
occurred on the day of injection, which could be related to the EH.
However, they were all mild and recovered on the same day or the next
day without any treatment. The slight prolongation of APTT suggested
that a little of hirudin was released with the increase of EH loading,
but the hirudin level in healthy subjects remained at a low level after
continuous administration, indicating that EH was generally safe in
healthy adults.
Furthermore, fibrin D-dimer increase and fibrinogen decrease were found
in several cases during the study. Many studies28-30indicated that levels of D-dimer were typically elevated with acute VTE.
However, D-dimer levels may also increase in a variety of nonthrombotic
disorders such as lipemia, hyperbilirubinemia, and hemolysis. In
hospitalized and other acutely ill patients commonly affected, D-dimer
testing had less utility because of the high frequency of false-positive
results. So the meaning of D-dimer increase in this study need to be
further investigated in the next clinical study. The decrease of
fibrinogen in this study was hard to explained with the mechanisms
associated with a reduction in fibrinogen concentration: hemodilution,
consumption, and degradation. However, the of fibrinogen decrease can be
demonstrated by evaluation of D-dimer, the other fibrin degradation
product31-33.