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.