2.2.1 Determination of the EH dose escalation range
According to the ”Guidelines for Estimating the Maximum Recommended Starting Dose of Drugs for the First Clinical Trial of Healthy Adult Volunteers” promulgated by the CENTER FOR DRUG EVALUATION and the No Observed Adverse Effect Level (NOAEL) calculation results of preclinical animal trials, it was known that the most suitable NOAEL of EH for long-term toxicity testing of cynomolgus monkeys was 1.3 mg/kg. The recommended clinical dose of REFLUDAN,20a similar drug from Bayer, approved by the FDA on March 6, 1998, for the treatment of HIT (Heparin-Induced Thrombocytopenia) was 0.4 mg/kg intravenous bolus first, and then 0.15 mg/kg/h of continuous intravenous drip for 2-7 days. Preclinical studies of EH showed that 0.4mg/kg of hirudin was equivalent to 0.416mg/kg EH, and the pharmacodynamic dose range of EH animal test was about 0.06~2.13mg/kg. The preclinical mouse and cynomolgus acute toxicity test of this drug showed that its Maximum Tolerated Dose (MTD) was much higher than the planned clinical effective dose. It was safe and reasonable to initially consider 0.2~2.0mg/kg as the dose increase range of this clinical trial.